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Sample records for cell wall-acting antibiotics

  1. Isolated cell behavior drives the evolution of antibiotic resistance.

    PubMed

    Artemova, Tatiana; Gerardin, Ylaine; Dudley, Carmel; Vega, Nicole M; Gore, Jeff

    2015-07-29

    Bacterial antibiotic resistance is typically quantified by the minimum inhibitory concentration (MIC), which is defined as the minimal concentration of antibiotic that inhibits bacterial growth starting from a standard cell density. However, when antibiotic resistance is mediated by degradation, the collective inactivation of antibiotic by the bacterial population can cause the measured MIC to depend strongly on the initial cell density. In cases where this inoculum effect is strong, the relationship between MIC and bacterial fitness in the antibiotic is not well defined. Here, we demonstrate that the resistance of a single, isolated cell-which we call the single-cell MIC (scMIC)-provides a superior metric for quantifying antibiotic resistance. Unlike the MIC, we find that the scMIC predicts the direction of selection and also specifies the antibiotic concentration at which selection begins to favor new mutants. Understanding the cooperative nature of bacterial growth in antibiotics is therefore essential in predicting the evolution of antibiotic resistance.

  2. Side Effects of Culture Media Antibiotics on Cell Differentiation.

    PubMed

    Llobet, Laura; Montoya, Julio; López-Gallardo, Ester; Ruiz-Pesini, Eduardo

    2015-11-01

    Besides the advance in scientific knowledge and the production of different compounds, cell culture can now be used to obtain cells for regenerative medicine. To avoid microbial contamination, antibiotics were usually incorporated into culture media. However, these compounds affect cell biochemistry and may modify the differentiation potential of cultured cells. To check this possibility, we grew human adipose tissue-derived stem cells and differentiated them to adipocyte with or without antibiotics commonly used in these culture protocols, such as a penicillin-streptomycin-amphotericin mix or gentamicin. We show that these antibiotics affect cell differentiation. Therefore, antibiotics should not be used in cell culture because aseptic techniques make these compounds unnecessary.

  3. Antibiotics

    MedlinePlus

    Antibiotics are powerful medicines that fight bacterial infections. Used properly, antibiotics can save lives. They either kill bacteria or ... natural defenses can usually take it from there. Antibiotics do not fight infections caused by viruses, such ...

  4. Cytotoxic effects of four antibiotics on endothelial cells.

    PubMed

    Lanbeck, P; Paulsen, O

    1995-12-01

    Intravenous administration of antibiotics often causes local pain and thrombophlebitis at the site of injection. An in vitro model that could predict these effects would be of great value. In this study the effects of four antibiotics, benzylpenicillin, cefuroxime, dicloxacillin and erythromycin, have been evaluated on three types of endothelial cells in culture. The cell types employed were primary culture from human umbilical vein, primary culture from bovine aorta, and the cell line EA-hy 926, a hybride endothelial cell. These cells were exposed to antibiotics for 24 hr and subsequently toxic effects on cells were evaluated by three different assays. Benzylpenicillin was atoxic in all types of cells and in all assays, in contrast to the other antibiotics. The other three antibiotics exerted dose dependent toxic effects in all investigated cells when DNA-synthesis and total cell protein were used as toxicity assays but the results varied between the cell types. There were no significant differences between the effects of cefuroxime, dicloxacillin and erythromycin on bovine endothelial cells. In the other cell types, however, there were significant differences between some drugs but the outcome depended on the cell type. It is concluded that it is possible to show differences between the effect of antibiotics on endothelial cells, but the result depends on the cell type employed.

  5. Isolated cell behavior drives the evolution of antibiotic resistance

    PubMed Central

    Artemova, Tatiana; Gerardin, Ylaine; Dudley, Carmel; Vega, Nicole M; Gore, Jeff

    2015-01-01

    Bacterial antibiotic resistance is typically quantified by the minimum inhibitory concentration (MIC), which is defined as the minimal concentration of antibiotic that inhibits bacterial growth starting from a standard cell density. However, when antibiotic resistance is mediated by degradation, the collective inactivation of antibiotic by the bacterial population can cause the measured MIC to depend strongly on the initial cell density. In cases where this inoculum effect is strong, the relationship between MIC and bacterial fitness in the antibiotic is not well defined. Here, we demonstrate that the resistance of a single, isolated cell—which we call the single-cell MIC (scMIC)—provides a superior metric for quantifying antibiotic resistance. Unlike the MIC, we find that the scMIC predicts the direction of selection and also specifies the antibiotic concentration at which selection begins to favor new mutants. Understanding the cooperative nature of bacterial growth in antibiotics is therefore essential in predicting the evolution of antibiotic resistance. PMID:26227664

  6. Mutations in mmpL and in the cell wall stress stimulon contribute to resistance to oxadiazole antibiotics in methicillin-resistant Staphylococcus aureus.

    PubMed

    Xiao, Qiaobin; Vakulenko, Sergei; Chang, Mayland; Mobashery, Shahriar

    2014-10-01

    Staphylococcus aureus is a leading cause of hospital- and community-acquired infections, which exhibit broad resistance to various antibiotics. We recently disclosed the discovery of the oxadiazole class of antibiotics, which has in vitro and in vivo activities against methicillin-resistant S. aureus (MRSA). We report herein that MmpL, a putative member of the resistance, nodulation, and cell division (RND) family of proteins, contributes to oxadiazole resistance in the S. aureus strain COL. Through serial passages, we generated two S. aureus COL variants that showed diminished susceptibilities to an oxadiazole antibiotic. The MICs for the oxadiazole against one strain (designated S. aureus COL(I)) increased reproducibly 2-fold (to 4 μg/ml), while against the other strain (S. aureus COL(R)), they increased >4-fold (to >8 μg/ml, the limit of solubility). The COL(R) strain was derived from the COL(I) strain. Whole-genome sequencing revealed 31 mutations in S. aureus COL(R), of which 29 were shared with COL(I). Consistent with our previous finding that oxadiazole antibiotics inhibit cell wall biosynthesis, we found 13 mutations that occurred either in structural genes or in promoters of the genes of the cell wall stress stimulon. Two unique mutations in S. aureus COL(R) were substitutions in two genes that encode the putative thioredoxin (SACOL1794) and MmpL (SACOL2566). A role for mmpL in resistance to oxadiazoles was discerned from gene deletion and complementation experiments. To our knowledge, this is the first report that a cell wall-acting antibiotic selects for mutations in the cell wall stress stimulon and the first to implicate MmpL in resistance to antibiotics in S. aureus.

  7. Comparative antibiotic eradication of mycoplasma infections from continuous cell lines.

    PubMed

    Uphoff, Cord C; Drexler, Hans G

    2002-02-01

    Accumulating data implicate mycoplasma contamination as the single biggest problem in the culture of continuous cell lines. Mycoplasma infection can affect virtually every parameter and functional activity of the eukaryotic cells. A successful alternative to discarding infected cultures is to attempt to eliminate the contaminants by treatment with specific and efficient antimycoplasma antibiotics. The addition of antibiotics to the culture medium during a limited period of time (1-3 wk) is a simple, inexpensive, and very practical approach for decontaminating continuous cell lines. Here, we examined the effectiveness of several antibiotic treatment protocols that we have employed routinely in our cell lines bank. On an aggregate, 673 cultures from 236 chronically mycoplasma-positive cell lines were exposed to one of the following five antibiotic regimens: mycoplasma removal agent (quinolone; a 1-wk treatment), enrofloxacin (quinolone; 1 wk), sparfloxacin (quinolone; 1 wk), ciprofloxacin (quinolone; 2 wk), and BM-Cyclin (alternating tiamulin and minocycline; 3 wk). The mycoplasma infection was permanently (as determined by three solid mycoplasma detection assays) eliminated by the various antibiotics in 66-85% of the cultures treated. Mycoplasma resistance was seen in 7-21%, and loss of the culture as a result of cytotoxically caused cell death occurred in 3-11% of the cultures treated. Overall, 223 of the 236 mycoplasma-positive cell lines could be cured in a first round of antibiotic treatment with at least one regimen. Taken together, 95% of the mycoplasma-infected cell lines were permanently cleansed of the contaminants by antibiotic treatment, which validates this approach as an efficient and technically simple mycoplasma eradication method.

  8. Comparative antibiotic eradication of mycoplasma infections from continuous cell lines.

    PubMed

    Uphoff, Cord C; Drexler, Hans G

    2002-02-01

    Accumulating data implicate mycoplasma contamination as the single biggest problem in the culture of continuous cell lines. Mycoplasma infection can affect virtually every parameter and functional activity of the eukaryotic cells. A successful alternative to discarding infected cultures is to attempt to eliminate the contaminants by treatment with specific and efficient antimycoplasma antibiotics. The addition of antibiotics to the culture medium during a limited period of time (1-3 wk) is a simple, inexpensive, and very practical approach for decontaminating continuous cell lines. Here, we examined the effectiveness of several antibiotic treatment protocols that we have employed routinely in our cell lines bank. On an aggregate, 673 cultures from 236 chronically mycoplasma-positive cell lines were exposed to one of the following five antibiotic regimens: mycoplasma removal agent (quinolone; a 1-wk treatment), enrofloxacin (quinolone; 1 wk), sparfloxacin (quinolone; 1 wk), ciprofloxacin (quinolone; 2 wk), and BM-Cyclin (alternating tiamulin and minocycline; 3 wk). The mycoplasma infection was permanently (as determined by three solid mycoplasma detection assays) eliminated by the various antibiotics in 66-85% of the cultures treated. Mycoplasma resistance was seen in 7-21%, and loss of the culture as a result of cytotoxically caused cell death occurred in 3-11% of the cultures treated. Overall, 223 of the 236 mycoplasma-positive cell lines could be cured in a first round of antibiotic treatment with at least one regimen. Taken together, 95% of the mycoplasma-infected cell lines were permanently cleansed of the contaminants by antibiotic treatment, which validates this approach as an efficient and technically simple mycoplasma eradication method. PMID:11929000

  9. Cell density and mobility protect swarming bacteria against antibiotics.

    PubMed

    Butler, Mitchell T; Wang, Qingfeng; Harshey, Rasika M

    2010-02-23

    Swarming bacteria move in multicellular groups and exhibit adaptive resistance to multiple antibiotics. Analysis of this phenomenon has revealed the protective power of high cell densities to withstand exposure to otherwise lethal antibiotic concentrations. We find that high densities promote bacterial survival, even in a nonswarming state, but that the ability to move, as well as the speed of movement, confers an added advantage, making swarming an effective strategy for prevailing against antimicrobials. We find no evidence of induced resistance pathways or quorum-sensing mechanisms controlling this group resistance, which occurs at a cost to cells directly exposed to the antibiotic. This work has relevance to the adaptive antibiotic resistance of bacterial biofilms.

  10. Cell motility and antibiotic tolerance of bacterial swarms

    NASA Astrophysics Data System (ADS)

    Zuo, Wenlong

    Many bacteria species can move across moist surfaces in a coordinated manner known as swarming. It is reported that swarm cells show higher tolerance to a wide variety of antibiotics than planktonic cells. We used the model bacterium E. coli to study how motility affects the antibiotic tolerance of swarm cells. Our results provide new insights for the control of pathogenic invasion via regulating cell motility. Mailing address: Room 306 Science Centre North Block, The Chinese University of Hong Kong, Shatin, N.T. Hong Kong SAR. Phone: +852-3943-6354. Fax: +852-2603-5204. E-mail: zwlong@live.com.

  11. Novel whole-cell antibiotic biosensors for compound discovery.

    PubMed

    Urban, Andreas; Eckermann, Stefan; Fast, Beate; Metzger, Susanne; Gehling, Matthias; Ziegelbauer, Karl; Rübsamen-Waigmann, Helga; Freiberg, Christoph

    2007-10-01

    Cells containing reporters which are specifically induced via selected promoters are used in pharmaceutical drug discovery and in environmental biology. They are used in screening for novel drug candidates and in the detection of bioactive compounds in environmental samples. In this study, we generated and validated a set of five Bacillus subtilis promoters fused to the firefly luciferase reporter gene suitable for cell-based screening, enabling the as yet most-comprehensive high-throughput diagnosis of antibiotic interference in the major biosynthetic pathways of bacteria: the biosynthesis of DNA by the yorB promoter, of RNA by the yvgS promoter, of proteins by the yheI promoter, of the cell wall by the ypuA promoter, and of fatty acids by the fabHB promoter. The reporter cells mainly represent novel antibiotic biosensors compatible with high-throughput screening. We validated the strains by developing screens with a set of 14,000 pure natural products, representing a source of highly diverse chemical entities, many of them with antibiotic activity (6% with anti-Bacillus subtilis activity of antibiotic ferrimycin A1 selectively inhibits protein biosynthesis.

  12. T Regulatory Cell Numbers and Function in Patients with Antibiotic-Refractory or Antibiotic-Responsive Lyme Arthritis

    PubMed Central

    Shen, Shiqian; Shin, Junghee J.; Strle, Klemen; McHugh, Gail; Li, Xin; Glickstein, Lisa J.; Drouin, Elise E.; Steere, Allen C.

    2010-01-01

    Objective In a murine model of antibiotic-refractory Lyme arthritis, the numbers of T regulatory cells (Treg) are dramatically reduced. Our goal was to examine Treg numbers and function in human patients with antibiotic-refractory Lyme arthritis. Methods CD4+ T cell subsets were enumerated in peripheral blood (PB) and synovial fluid (SF) in 12 patients with antibiotic-refractory arthritis and 6 with antibiotic-responsive arthritis. Treg function was examined using Borrelia-specific and non-specific Treg proliferation assays. Results In both patient groups, IFN-γ+ TH1 cells in SF were abundant and enriched (~50% of CD4+ T cells). In patients with antibiotic-refractory arthritis, the median percentages of FoxP3+ Treg were significantly higher in SF than PB (12% versus 6%) (P<0.01) or in SF in patients with antibiotic-responsive arthritis (12% versus 5%) (P=0.04). Moreover, in the refractory group, a higher percentage of Treg in SF correlated with a shorter duration to resolution of arthritis (r = −0.74, P = 0.006). In contrast, patients with fewer Treg had suboptimal responses to DMARDs and longer duration of arthritis after antibiotics, and they often required synovectomies for arthritis resolution. In each group, Treg in SF dampened B. burgdorferi-specific proliferative responses, and in 2 patients with refractory arthritis, Treg were functional in non-specific suppression assays. Conclusions Treg were functional in patients with antibiotic-refractory arthritis, and in some patients, large numbers of these cells in SF appeared to participate in arthritis resolution. However, as in the murine model, patients with refractory arthritis and low numbers of Treg seemed unable to resolve synovial inflammation. PMID:20506317

  13. Endothelial Cell Toxicity of Vancomycin Infusion Combined with Other Antibiotics

    PubMed Central

    Drouet, Maryline; Chai, Feng; Barthélémy, Christine; Lebuffe, Gilles; Debaene, Bertrand; Odou, Pascal

    2015-01-01

    French guidelines recommend central intravenous (i.v.) infusion for high concentrations of vancomycin, but peripheral intravenous (p.i.v.) infusion is often preferred in intensive care units. Vancomycin infusion has been implicated in cases of phlebitis, with endothelial toxicity depending on the drug concentration and the duration of the infusion. Vancomycin is frequently infused in combination with other i.v. antibiotics through the same administrative Y site, but the local toxicity of such combinations has been poorly evaluated. Such an assessment could improve vancomycin infusion procedures in hospitals. Human umbilical vein endothelial cells (HUVEC) were challenged with clinical doses of vancomycin over 24 h with or without other i.v. antibiotics. Cell death was measured with the alamarBlue test. We observed an excess cellular death rate without any synergistic effect but dependent on the numbers of combined infusions when vancomycin and erythromycin or gentamicin were infused through the same Y site. Incompatibility between vancomycin and piperacillin-tazobactam was not observed in our study, and rinsing the cells between the two antibiotic infusions did not reduce endothelial toxicity. No endothelial toxicity of imipenem-cilastatin was observed when combined with vancomycin. p.i.v. vancomycin infusion in combination with other medications requires new recommendations to prevent phlebitis, including limiting coinfusion on the same line, reducing the infusion rate, and choosing an intermittent infusion method. Further studies need to be carried out to explore other drug combinations in long-term vancomycin p.i.v. therapy so as to gain insight into the mechanisms of drug incompatibility under multidrug infusion conditions. PMID:26055373

  14. Resistance to antibiotics targeted to the bacterial cell wall

    PubMed Central

    Nikolaidis, I; Favini-Stabile, S; Dessen, A

    2014-01-01

    Peptidoglycan is the main component of the bacterial cell wall. It is a complex, three-dimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed. PMID:24375653

  15. Antibiotic regimen based on population analysis of residing persister cells eradicates Staphylococcus epidermidis biofilms

    PubMed Central

    Yang, Shoufeng; Hay, Iain D.; Cameron, David R.; Speir, Mary; Cui, Bintao; Su, Feifei; Peleg, Anton Y.; Lithgow, Trevor; Deighton, Margaret A.; Qu, Yue

    2015-01-01

    Biofilm formation is a major pathogenicity strategy of Staphylococcus epidermidis causing various medical-device infections. Persister cells have been implicated in treatment failure of such infections. We sought to profile bacterial subpopulations residing in S. epidermidis biofilms, and to establish persister-targeting treatment strategies to eradicate biofilms. Population analysis was performed by challenging single biofilm cells with antibiotics at increasing concentrations ranging from planktonic minimum bactericidal concentrations (MBCs) to biofilm MBCs (MBCbiofilm). Two populations of “persister cells” were observed: bacteria that survived antibiotics at MBCbiofilm for 24/48 hours were referred to as dormant cells; those selected with antibiotics at 8 X MICs for 3 hours (excluding dormant cells) were defined as tolerant-but-killable (TBK) cells. Antibiotic regimens targeting dormant cells were tested in vitro for their efficacies in eradicating persister cells and intact biofilms. This study confirmed that there are at least three subpopulations within a S. epidermidis biofilm: normal cells, dormant cells, and TBK cells. Biofilms comprise more TBK cells and dormant cells than their log-planktonic counterparts. Using antibiotic regimens targeting dormant cells, i.e. effective antibiotics at MBCbiofilm for an extended period, might eradicate S. epidermidis biofilms. Potential uses for this strategy are in antibiotic lock techniques and inhaled aerosolized antibiotics. PMID:26687035

  16. Dielectrophoretic characterization of antibiotic-treated Mycobacterium tuberculosis complex cells.

    PubMed

    Inoue, Shinnosuke; Lee, Hyun-Boo; Becker, Annie L; Weigel, Kris M; Kim, Jong-Hoon; Lee, Kyong-Hoon; Cangelosi, Gerard A; Chung, Jae-Hyun

    2015-10-01

    Multi-drug resistant tuberculosis (MDR-TB) has become a serious concern for proper treatment of patients. As a phenotypic method, dielectrophoresis can be useful but is yet to be attempted to evaluate Mycobacterium tuberculosis complex cells. This paper investigates the dielectrophoretic behavior of Mycobacterium bovis (Bacillus Calmette-Guérin, BCG) cells that are treated with heat or antibiotics rifampin (RIF) or isoniazid (INH). The experimental parameters are designed on the basis of our sensitivity analysis. The medium conductivity (σ(m)) and the frequency (f) for a crossover frequency (f(xo1)) test are decided to detect the change of σ(m)-f(xo1) in conjunction with the drug mechanism. Statistical modeling is conducted to estimate the distributions of viable and nonviable cells from the discrete measurement of f (xo1). Finally, the parameters of the electrophysiology of BCG cells, C(envelope) and σ(cyto), are extracted through a sampling algorithm. This is the first evaluation of the dielectrophoresis (DEP) approach as a means to assess the effects of antimicrobial drugs on M. tuberculosis complex cells.

  17. A cell wall damage response mediated by a sensor kinase/response regulator pair enables beta-lactam tolerance.

    PubMed

    Dörr, Tobias; Alvarez, Laura; Delgado, Fernanda; Davis, Brigid M; Cava, Felipe; Waldor, Matthew K

    2016-01-12

    The bacterial cell wall is critical for maintenance of cell shape and survival. Following exposure to antibiotics that target enzymes required for cell wall synthesis, bacteria typically lyse. Although several cell envelope stress response systems have been well described, there is little knowledge of systems that modulate cell wall synthesis in response to cell wall damage, particularly in Gram-negative bacteria. Here we describe WigK/WigR, a histidine kinase/response regulator pair that enables Vibrio cholerae, the cholera pathogen, to survive exposure to antibiotics targeting cell wall synthesis in vitro and during infection. Unlike wild-type V. cholerae, mutants lacking wigR fail to recover following exposure to cell-wall-acting antibiotics, and they exhibit a drastically increased cell diameter in the absence of such antibiotics. Conversely, overexpression of wigR leads to cell slimming. Overexpression of activated WigR also results in increased expression of the full set of cell wall synthesis genes and to elevated cell wall content. WigKR-dependent expression of cell wall synthesis genes is induced by various cell-wall-acting antibiotics as well as by overexpression of an endogenous cell wall hydrolase. Thus, WigKR appears to monitor cell wall integrity and to enhance the capacity for increased cell wall production in response to damage. Taken together, these findings implicate WigKR as a regulator of cell wall synthesis that controls cell wall homeostasis in response to antibiotics and likely during normal growth as well.

  18. Antibiotic Transport in Resistant Bacteria: Synchrotron UV Fluorescence Microscopy to Determine Antibiotic Accumulation with Single Cell Resolution

    PubMed Central

    Kaščáková, Slávka; Maigre, Laure; Chevalier, Jacqueline; Réfrégiers, Matthieu; Pagès, Jean-Marie

    2012-01-01

    A molecular definition of the mechanism conferring bacterial multidrug resistance is clinically crucial and today methods for quantitative determination of the uptake of antimicrobial agents with single cell resolution are missing. Using the naturally occurring fluorescence of antibacterial agents after deep ultraviolet (DUV) excitation, we developed a method to non-invasively monitor the quinolones uptake in single bacteria. Our approach is based on a DUV fluorescence microscope coupled to a synchrotron beamline providing tuneable excitation from 200 to 600 nm. A full spectrum was acquired at each pixel of the image, to study the DUV excited fluorescence emitted from quinolones within single bacteria. Measuring spectra allowed us to separate the antibiotic fluorescence from the autofluorescence contribution. By performing spectroscopic analysis, the quantification of the antibiotic signal was possible. To our knowledge, this is the first time that the intracellular accumulation of a clinical antibitiotic could be determined and discussed in relation with the level of drug susceptibility for a multiresistant strain. This method is especially important to follow the behavior of quinolone molecules at individual cell level, to quantify the intracellular concentration of the antibiotic and develop new strategies to combat the dissemination of MDR-bacteria. In addition, this original approach also indicates the heterogeneity of bacterial population when the same strain is under environmental stress like antibiotic attack. PMID:22719907

  19. An azido-oxazolidinone antibiotic for live bacterial cell imaging and generation of antibiotic variants

    PubMed Central

    Phetsang, Wanida; Blaskovich, Mark A.T.; Butler, Mark S.; Huang, Johnny X.; Zuegg, Johannes; Mamidyala, Sreeman K.; Ramu, Soumya; Kavanagh, Angela M.; Cooper, Matthew A.

    2014-01-01

    An azide-functionalised analogue of the oxazolidinone antibiotic linezolid was synthesised and shown to retain antimicrobial activity. Using facile ‘click’ chemistry, this versatile intermediate can be further functionalised to explore antimicrobial structure–activity relationships or conjugated to fluorophores to generate fluorescent probes. Such probes can report bacteria and their location in a sample in real time. Modelling of the structures bound to the cognate 50S ribosome target demonstrates binding to the same site as linezolid is possible. The fluorescent probes were successfully used to image Gram-positive bacteria using confocal microscopy. PMID:25023540

  20. Unraveling the genetic driving forces enabling antibiotic resistance at the single cell level

    NASA Astrophysics Data System (ADS)

    Bos, Julia

    Bacteria are champions at finding ways to quickly respond and adapt to environments like the human gut, known as the epicentre of antibiotic resistance. How do they do it? Combining molecular biology tools to microfluidic and fluorescence microscopy technologies, we monitor the behavior of bacteria at the single cell level in the presence of non-toxic doses of antibiotics. By tracking the chromosome dynamics of Escherichia coli cells upon antibiotic treatment, we examine the changes in the number, localization and content of the chromosome copies within one cell compartment or between adjacent cells. I will discuss how our work pictures the bacterial genomic plasticity as a driving force in evolution and how it provides access to the mechanisms controlling the subtle balance between genetic diversity and stability in the development of antibiotic resistance.

  1. Decline in the frequencies of Borrelia burgdorferi OspA161 175-specific T cells after antibiotic therapy in HLA-DRB1*0401-positive patients with antibiotic-responsive or antibiotic-refractory lyme arthritis.

    PubMed

    Kannian, Priya; Drouin, Elise E; Glickstein, Lisa; Kwok, William W; Nepom, Gerald T; Steere, Allen C

    2007-11-01

    Synovitis in patients with antibiotic-refractory Lyme arthritis persists for months to several years after antibiotic therapy. This course, which may result from infection-induced autoimmunity, is associated with T cell recognition of Borrelia burgdorferi outer surface protein A (OspA(161-175)) and with HLA-DR molecules that bind this epitope, including the DRB1*0401 molecule. In this study, we used tetramer reagents to determine the frequencies of OspA(161-175)-specific T cells in samples of PBMC and synovial fluid mononuclear cells (SFMC) from 13 DRB1*0401-positive patients with antibiotic-responsive or antibiotic-refractory arthritis. Initially, three of the six patients (50%) with antibiotic-responsive arthritis and four of the seven patients (57%) with antibiotic-refractory arthritis had frequencies of OspA(161-175)-specific CD4(+) T cells in peripheral blood above the cutoff value of 4 per 10(5) cells. Among the five patients with concomitant PBMC and SFMC, four (80%) had OspA tetramer-positive cells at both sites, but the mean frequency of such cells was 16 times higher in SFMC, reaching levels as high as 1,177 per 10(5) cells. In the two patients in each patient group in whom serial samples were available, the frequencies of OspA(161-175)-specific T cells declined to low or undetectable levels during or soon after antibiotic therapy, months before the resolution of synovitis in the two patients with antibiotic-refractory arthritis. Thus, the majority of patients with Lyme arthritis initially have increased frequencies of OspA(161-175)-specific T cells. However, the marked decline in the frequency of such cells with antibiotic therapy suggests that persistent synovitis in the refractory group is not perpetuated by these cells.

  2. Single-Cell Tracking Reveals Antibiotic-Induced Changes in Mycobacterial Energy Metabolism

    PubMed Central

    Özdemir, Emre; McKinney, John D.

    2015-01-01

    ABSTRACT ATP is a key molecule of cell physiology, but despite its importance, there are currently no methods for monitoring single-cell ATP fluctuations in live bacteria. This is a major obstacle in studies of bacterial energy metabolism, because there is a growing awareness that bacteria respond to stressors such as antibiotics in a highly individualistic manner. Here, we present a method for long-term single-cell tracking of ATP levels in Mycobacterium smegmatis based on a combination of microfluidics, time-lapse microscopy, and Förster resonance energy transfer (FRET)-based ATP biosensors. Upon treating cells with antibiotics, we observed that individual cells undergo an abrupt and irreversible switch from high to low intracellular ATP levels. The kinetics and extent of ATP switching clearly discriminate between an inhibitor of ATP synthesis and other classes of antibiotics. Cells that resume growth after 24 h of antibiotic treatment maintain high ATP levels throughout the exposure period. In contrast, antibiotic-treated cells that switch from ATP-high to ATP-low states never resume growth after antibiotic washout. Surprisingly, only a subset of these nongrowing ATP-low cells stains with propidium iodide (PI), a widely used live/dead cell marker. These experiments also reveal a cryptic subset of cells that do not resume growth after antibiotic washout despite remaining ATP high and PI negative. We conclude that ATP tracking is a more dynamic, sensitive, reliable, and discriminating marker of cell viability than staining with PI. This method could be used in studies to evaluate antimicrobial effectiveness and mechanism of action, as well as for high-throughput screening. PMID:25691591

  3. [Effect of Stress on Emergence of Antibiotic-resistant Escherichia coli Cells].

    PubMed

    Loiko, N G; Kozlova, A N; Nikolaev, Yu A; Gaponov, A M; Tutel'yan, A V; El'-Registan, G I

    2015-01-01

    Effect of sublethal doses of physical and chemical stressors (heat shock for 2 h at 45 degrees C and addition of C12-alkylhydroxybenzene, a microbial alarmone) on development of resistance to the subsequent lethal antibiotic attack and the role of the time interval between these treatments were studied on a submerged batch culture of Escherichia coli 12. The interval sufficient for the development of stress response provides for development of temporary adaptive resistance to the antibiotic attack, resulting in increased number of surviving persister cells. The interval below the time required for the stress response potentiates cell death and results in a decreased number of persisters. Heterogeneity of the fractions (10(-4) to 10(-2)% of the intial CFU number) surviving lethal doses of an antibiotic (a mpicillin or ciprofloxacin) was found. Apart from a low number of antibiotic-resistant cells (up to 0.005% of surviving cells), the fractions contained antibiotic-tolerant forms, such as temporarily resistant metabolically adapted cells, long-term persisters, and the cells of slowly growing SCV variants with small colonies (d ≤ 1 mm). Persisters are hypothesized to act as precursors for cystlike dormant cells (CLC), in which the cell differentiation stage is completed and the processes of cell ametabolism (transition to the anabiotic state) are still incomplete. PMID:27169240

  4. Thiazole Antibiotics Target FoxM1 and Induce Apoptosis in Human Cancer Cells

    PubMed Central

    Bhat, Uppoor G.; Halasi, Marianna; Gartel, Andrei L.

    2009-01-01

    Forkhead box M1 (FoxM1) oncogenic transcription factor represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Recently, using a cell-based assay system we identified thiazole antibiotic Siomycin A as an inhibitor of FoxM1 transcriptional activity. Here, we report that structurally similar thiazole antibiotic, thiostrepton also inhibits the transcriptional activity of FoxM1. Furthermore, we found that these thiopeptides did not inhibit the transcriptional activity of other members of the Forkhead family or some non-related transcription factors. Further experiments revealed that thiazole antibiotics also inhibit FoxM1 expression, but not the expression of other members of the Forkhead box family. In addition, we found that the thiazole antibiotics efficiently inhibited the growth and induced potent apoptosis in human cancer cell lines of different origin. Thiopeptide-induced apoptosis correlated with the suppression of FoxM1 expression, while overexpression of FoxM1 partially protected cancer cells from the thiazole antibiotic-mediated cell death. These data suggest that Siomycin A and thiostrepton may specifically target FoxM1 to induce apoptosis in cancer cells and FoxM1 inhibitors/thiazole antibiotics could be potentially developed as novel anticancer drugs against human neoplasia. PMID:19440351

  5. Mathematical Modeling and Nonlinear Dynamical Analysis of Cell Growth in Response to Antibiotics

    NASA Astrophysics Data System (ADS)

    Jin, Suoqin; Niu, Lili; Wang, Gang; Zou, Xiufen

    2015-06-01

    This study is devoted to the revelation of the dynamical mechanisms of cell growth in response to antibiotics. We establish a mathematical model of ordinary differential equations for an antibiotic-resistant growth system with one positive feedback loop. We perform a dynamical analysis of the behavior of this model system. We present adequate sets of conditions that can guarantee the existence and stability of biologically-reasonable steady states. Using bifurcation analysis and numerical simulation, we show that the relative growth rate, which is defined as the ratio of the cell growth rate to the basal cell growth rate in the absence of antibiotics, can exhibit bistable behavior in an extensive range of parameters that correspond to a growth state and a nongrowth state in biology. We discover that both antibiotic and antibiotic resistance genes can cooperatively enhance bistability, whereas the cooperative coefficient of feedback can contribute to the onset of bistability. These results would contribute to a better understanding of not only the evolution of antibiotics but also the emergence of drug resistance in other diseases.

  6. Microspectrometric insights on the uptake of antibiotics at the single bacterial cell level.

    PubMed

    Cinquin, Bertrand; Maigre, Laure; Pinet, Elizabeth; Chevalier, Jacqueline; Stavenger, Robert A; Mills, Scott; Réfrégiers, Matthieu; Pagès, Jean-Marie

    2015-12-11

    Bacterial multidrug resistance is a significant health issue. A key challenge, particularly in Gram-negative antibacterial research, is to better understand membrane permeation of antibiotics in clinically relevant bacterial pathogens. Passing through the membrane barrier to reach the required concentration inside the bacterium is a pivotal step for most antibacterials. Spectrometric methodology has been developed to detect drugs inside bacteria and recent studies have focused on bacterial cell imaging. Ultimately, we seek to use this method to identify pharmacophoric groups which improve penetration, and therefore accumulation, of small-molecule antibiotics inside bacteria. We developed a method to quantify the time scale of antibiotic accumulation in living bacterial cells. Tunable ultraviolet excitation provided by DISCO beamline (synchrotron Soleil) combined with microscopy allows spectroscopic analysis of the antibiotic signal in individual bacterial cells. Robust controls and measurement of the crosstalk between fluorescence channels can provide real time quantification of drug. This technique represents a new method to assay drug translocation inside the cell and therefore incorporate rational drug design to impact antibiotic uptake.

  7. Microspectrometric insights on the uptake of antibiotics at the single bacterial cell level

    PubMed Central

    Cinquin, Bertrand; Maigre, Laure; Pinet, Elizabeth; Chevalier, Jacqueline; Stavenger, Robert A.; Mills, Scott; Réfrégiers, Matthieu; Pagès, Jean-Marie

    2015-01-01

    Bacterial multidrug resistance is a significant health issue. A key challenge, particularly in Gram-negative antibacterial research, is to better understand membrane permeation of antibiotics in clinically relevant bacterial pathogens. Passing through the membrane barrier to reach the required concentration inside the bacterium is a pivotal step for most antibacterials. Spectrometric methodology has been developed to detect drugs inside bacteria and recent studies have focused on bacterial cell imaging. Ultimately, we seek to use this method to identify pharmacophoric groups which improve penetration, and therefore accumulation, of small-molecule antibiotics inside bacteria. We developed a method to quantify the time scale of antibiotic accumulation in living bacterial cells. Tunable ultraviolet excitation provided by DISCO beamline (synchrotron Soleil) combined with microscopy allows spectroscopic analysis of the antibiotic signal in individual bacterial cells. Robust controls and measurement of the crosstalk between fluorescence channels can provide real time quantification of drug. This technique represents a new method to assay drug translocation inside the cell and therefore incorporate rational drug design to impact antibiotic uptake. PMID:26656111

  8. Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities.

    PubMed

    Penesyan, Anahit; Gillings, Michael; Paulsen, Ian T

    2015-01-01

    Bacterial resistance is a rapidly escalating threat to public health as our arsenal of effective antibiotics dwindles. Therefore, there is an urgent need for new antibiotics. Drug discovery has historically focused on bacteria growing in planktonic cultures. Many antibiotics were originally developed to target individual bacterial cells, being assessed in vitro against microorganisms in a planktonic mode of life. However, towards the end of the 20th century it became clear that many bacteria live as complex communities called biofilms in their natural habitat, and this includes habitats within a human host. The biofilm mode of life provides advantages to microorganisms, such as enhanced resistance towards environmental stresses, including antibiotic challenge. The community level resistance provided by biofilms is distinct from resistance mechanisms that operate at a cellular level, and cannot be overlooked in the development of novel strategies to combat infectious diseases. The review compares mechanisms of antibiotic resistance at cellular and community levels in the light of past and present antibiotic discovery efforts. Future perspectives on novel strategies for treatment of biofilm-related infectious diseases are explored.

  9. Short-term effects of four antibiotics on DNA synthesis in endothelial cells.

    PubMed

    Lanbeck, P; Paulsen, O

    2001-04-01

    The irritating effect of parenterally administered antibiotics on vessels is a common clinical problem. In a previous study we found that solutions of three commonly used antibiotics, cefuroxime, erythromycin and dicloxacillin, exerted cytotoxic effects on endothelial cells after 24 hr exposure. In contrast benzylpenicillin did not have such effects. In the present study, endothelial cells of different origin were exposed to these four antibiotics at higher concentrations than in the previous investigation but only for 5, 30 and 60 min. Incorporation of 3H-thymidine in the cells as a measurement of DNA synthesis was used as cytotoxic assay. A concentration-dependent and time-related inhibition was found after exposure to erythromycin and dicloxacillin but not after exposure to cefuroxime and benzylpenicillin. The effects were similar on the three different cell types used in the experiments. This study demonstrates that the cytotoxic effects differ even after short-term exposure to the antibiotics. In contrast to the previous study, cefuroxime lacks cytotoxicity when endothelial cells are exposed for less than one hour. The short-term exposition model used in this study should be more predictive as it mimics in vivo conditions better.

  10. Antibiotic magainins exert cytolytic activity against transformed cell lines through channel formation.

    PubMed Central

    Cruciani, R A; Barker, J L; Zasloff, M; Chen, H C; Colamonici, O

    1991-01-01

    Magainins are an ionophoric class of vertebrate peptides with antibiotic activity against various microorganisms. Here we show that magainin 2 and synthetic analogues can rapidly and irreversibly lyse hematopoietic tumor and solid tumor target cells with a relative cytotoxic potency that parallels their antibacterial efficacy and at concentrations that are relatively nontoxic to well-differentiated cells. The cytotoxicity is prevented by cell depolarization. Magainins represent a natural cytolytic agent in vertebrates and may provide another therapeutic strategy for certain tumors. PMID:1708887

  11. Bacterial cell wall composition and the influence of antibiotics by cell-wall and whole-cell NMR.

    PubMed

    Romaniuk, Joseph A H; Cegelski, Lynette

    2015-10-01

    The ability to characterize bacterial cell-wall composition and structure is crucial to understanding the function of the bacterial cell wall, determining drug modes of action and developing new-generation therapeutics. Solid-state NMR has emerged as a powerful tool to quantify chemical composition and to map cell-wall architecture in bacteria and plants, even in the context of unperturbed intact whole cells. In this review, we discuss solid-state NMR approaches to define peptidoglycan composition and to characterize the modes of action of old and new antibiotics, focusing on examples in Staphylococcus aureus. We provide perspectives regarding the selected NMR strategies as we describe the exciting and still-developing cell-wall and whole-cell NMR toolkit. We also discuss specific discoveries regarding the modes of action of vancomycin analogues, including oritavancin, and briefly address the reconsideration of the killing action of β-lactam antibiotics. In such chemical genetics approaches, there is still much to be learned from perturbations enacted by cell-wall assembly inhibitors, and solid-state NMR approaches are poised to address questions of cell-wall composition and assembly in S. aureus and other organisms.

  12. Bacterial cell wall composition and the influence of antibiotics by cell-wall and whole-cell NMR

    PubMed Central

    Romaniuk, Joseph A. H.; Cegelski, Lynette

    2015-01-01

    The ability to characterize bacterial cell-wall composition and structure is crucial to understanding the function of the bacterial cell wall, determining drug modes of action and developing new-generation therapeutics. Solid-state NMR has emerged as a powerful tool to quantify chemical composition and to map cell-wall architecture in bacteria and plants, even in the context of unperturbed intact whole cells. In this review, we discuss solid-state NMR approaches to define peptidoglycan composition and to characterize the modes of action of old and new antibiotics, focusing on examples in Staphylococcus aureus. We provide perspectives regarding the selected NMR strategies as we describe the exciting and still-developing cell-wall and whole-cell NMR toolkit. We also discuss specific discoveries regarding the modes of action of vancomycin analogues, including oritavancin, and briefly address the reconsideration of the killing action of β-lactam antibiotics. In such chemical genetics approaches, there is still much to be learned from perturbations enacted by cell-wall assembly inhibitors, and solid-state NMR approaches are poised to address questions of cell-wall composition and assembly in S. aureus and other organisms. PMID:26370936

  13. Suppression of methanogenesis for hydrogen production in single-chamber microbial electrolysis cells using various antibiotics.

    PubMed

    Catal, Tunc; Lesnik, Keaton Larson; Liu, Hong

    2015-01-01

    Methanogens can utilize the hydrogen produced in microbial electrolysis cells (MECs), thereby decreasing the hydrogen generation efficiency. However, various antibiotics have previously been shown to inhibit methanogenesis. In the present study antibiotics, including neomycin sulfate, 2-bromoethane sulfonate, 2-chloroethane sulfonate, 8-aza-hypoxanthine, were examined to determine if hydrogen production could be improved through inhibition of methanogenesis but not hydrogen production in MECs. 1.1mM neomycin sulfate inhibited both methane and hydrogen production while 2-chloroethane sulfonate (20mM), 2-bromoethane sulfonate (20mM), and 8-aza-hypoxanthine (3.6mM) can inhibited methane generation and with concurrent increases in hydrogen production. Our results indicated that adding select antibiotics to the mixed species community in MECs could be a suitable method to enhance hydrogen production efficiency.

  14. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery

    PubMed Central

    Cho, Hongbaek; Uehara, Tsuyoshi; Bernhardt, Thomas G.

    2014-01-01

    SUMMARY Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality-control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development. PMID:25480295

  15. Asymmetry and aging of mycobacterial cells lead to variable growth and antibiotic susceptibility.

    PubMed

    Aldridge, Bree B; Fernandez-Suarez, Marta; Heller, Danielle; Ambravaneswaran, Vijay; Irimia, Daniel; Toner, Mehmet; Fortune, Sarah M

    2012-01-01

    Cells use both deterministic and stochastic mechanisms to generate cell-to-cell heterogeneity, which enables the population to better withstand environmental stress. Here we show that, within a clonal population of mycobacteria, there is deterministic heterogeneity in elongation rate that arises because mycobacteria grow in an unusual, unipolar fashion. Division of the asymmetrically growing mother cell gives rise to daughter cells that differ in elongation rate and size. Because the mycobacterial cell division cycle is governed by time, not cell size, rapidly elongating cells do not divide more frequently than slowly elongating cells. The physiologically distinct subpopulations of cells that arise through asymmetric growth and division are differentially susceptible to clinically important classes of antibiotics. PMID:22174129

  16. Studies on penetration of antibiotic in bacterial cells in space conditions (7-IML-1)

    NASA Technical Reports Server (NTRS)

    Tixador, R.

    1992-01-01

    The Cytos 2 experiment was performed aboard Salyut 7 in order to test the antibiotic sensitivity of bacteria cultivated in vitro in space. An increase of the Minimal Inhibitory Concentration (MIC) in the inflight cultures (i.e., an increase of the antibiotic resistance) was observed. Complementary studies of the ultrastructure showed a thickening of the cell envelope. In order to confirm the results of the Cytos 2 experiment, we performed the ANTIBIO experiment during the D1 mission to try to differentiate, by means of the 1 g centrifuge in the Biorack, between the biological effects of cosmic rays and those caused by microgravity conditions. The originality of this experiment was in the fact that it was designed to test the antibiotic sensitivity of bacteria cultivated in vitro during the orbital phase of the flight. The results show an increase in resistance to Colistin in in-flight bacteria. The MIC is practically double in the in-flight cultures. A cell count of living bacteria in the cultures containing the different Colistin concentrations showed a significant difference between the cultures developed during space flight and the ground based cultures. The comparison between the 1 g and 0 g in-flight cultures show similar behavior for the two sets. Nevertheless, a small difference between the two sets of ground based control cultures was noted. The cultures developed on the ground centrifuge (1.4 g) present a slight decrease in comparison with the cultures developed in the static rack (1 g). In order to approach the mechanisms of the increase of antibiotic resistance on bacteria cultivated in vitro in space, we have proposed the study on penetration of antibiotics in bacterial cells in space conditions. This experiment was selected for the International Microgravity Laboratory 1 (IML-1) mission.

  17. Reducing the Level of Undecaprenyl Pyrophosphate Synthase Has Complex Effects on Susceptibility to Cell Wall Antibiotics.

    PubMed

    Lee, Yong Heon; Helmann, John D

    2013-06-24

    Undecaprenyl pyrophosphate synthase (UppS) catalyzes the formation of the C55 lipid carrier (UPP) that is essential for bacterial peptidoglycan biosynthesis. Here we selected a vancomycin (VAN)-resistant derivative of Bacillus subtilis W168 which contains a single-point mutation in the ribosome-binding site (RBS) of the uppS gene designated uppS1. Genetic reconstruction experiments demonstrate that the uppS1 allele is sufficient to confer low-level VAN resistance and causes reduced UppS translation. The decreased level of UppS renders B. subtilis slightly more susceptible to many late-acting cell wall antibiotics including β-lactams, but significantly more resistant to fosfomycin and D-cycloserine, antibiotics that interfere with the very early steps of cell wall synthesis. We further show that the uppS1 allele leads to slightly elevated expression of the σ(M) regulon, possibly helping to compensate for the stress caused by a decrease in UPP levels. Notably, the uppS1 mutation increases resistance to VAN, fosfomycin, and D-cycloserine in wild-type cells, but this effect is greatly reduced or eliminated in a sigM mutant background. Our findings suggest that, although UppS is an attractive antibacterial target, incomplete inhibition of UppS function may lead to increased resistance to some cell wall-active antibiotics. PMID:23796923

  18. A validated measure of adherence to antibiotic prophylaxis in children with sickle cell disease

    PubMed Central

    Duncan, Natalie A; Kronenberger, William G; Hampton, Kisha C; Bloom, Ellen M; Rampersad, Angeli G; Roberson, Christopher P; Shapiro, Amy D

    2016-01-01

    Background Antibiotic prophylaxis is a mainstay in sickle cell disease management. However, adherence is estimated at only 66%. This study aimed to develop and validate a Sickle Cell Antibiotic Adherence Level Evaluation (SCAALE) to promote systematic and detailed adherence evaluation. Methods A 28-item questionnaire was created, covering seven adherence areas. General Adherence Ratings from the parent and one health care provider and medication possession ratios were obtained as validation measures. Results Internal consistency was very good to excellent for the total SCAALE (α=0.89) and four of the seven subscales. Correlations between SCAALE scores and validation measures were strong for the total SCAALE and five of the seven subscales. Conclusion The SCAALE provides a detailed, quantitative, multidimensional, and global measurement of adherence and can promote clinical care and research. PMID:27354768

  19. Nitrite Modulates Bacterial Antibiotic Susceptibility and Biofilm Formation in Association with Airway Epithelial Cells

    PubMed Central

    Zemke, Anna C; Shiva, Sruti; Burn, Jane L.; Moskowitz, Samuel M.; Pilewski, Joseph M.; Gladwin, Mark T.; Bomberger, Jennifer M.

    2014-01-01

    Pseudomonas aeruginosa is the major pathogenic bacteria in cystic fibrosis and other forms of bronchiectasis. Growth in antibiotic resistant biofilms contributes to the virulence of this organism. Sodium nitrite has antimicrobial properties and has been tolerated as a nebulized compound at high concentrations in human subjects with pulmonary hypertension; however, its effects have not been evaluated on biotic biofilms or in combination with other clinically useful antibiotics. We grew P. aeruginosa on the apical surface of primary human airway epithelial cells to test the efficacy of sodium nitrite against biotic biofilms. Nitrite alone prevented 99% of biofilm growth. We then identified significant cooperative interactions between nitrite and polymyxins. For P. aeruginosa growing on primary CF airway cells, combining nitrite and colistimethate resulted in an additional log of bacterial inhibition compared to treating with either agent alone. Nitrite and colistimethate additively inhibited oxygen consumption by P. aeruginosa. Surprisingly, while the antimicrobial effects of nitrite in planktonic, aerated cultures are nitric oxide (NO) dependent, antimicrobial effects in other growth conditions are not. The inhibitory effect of nitrite on bacterial oxygen consumption and biofilm growth did not require NO as an intermediate as chemically scavenging NO did not block growth inhibition. These data suggest an NO-radical independent nitrosative or oxidative inhibition of respiration. The combination of nebulized sodium nitrite and colistimethate may provide a novel therapy for chronic P. aeruginosa airway infections, because sodium nitrite, unlike other antibiotic respiratory chain ‘poisons’, can be safely nebulized at high concentration in humans. PMID:25229185

  20. A Novel Cell-Associated Protection Assay Demonstrates the Ability of Certain Antibiotics To Protect Ocular Surface Cell Lines from Subsequent Clinical Staphylococcus aureus Challenge▿†

    PubMed Central

    Wingard, J. B.; Romanowski, E. G.; Kowalski, R. P.; Mah, F. S.; Ling, Y.; Bilonick, R. A.; Shanks, R. M. Q.

    2011-01-01

    In vivo effectiveness of topical antibiotics may depend on their ability to associate with epithelial cells to provide continued protection, but this contribution is not measured by standard antibiotic susceptibility tests. We report a new in vitro method that measures the ability of test antibiotics azithromycin (AZM), erythromycin (ERY), tetracycline (TET), and bacitracin (BAC) to associate with mammalian cells and to protect these cells from destruction by bacteria. Mammalian cell lines were grown to confluence using antibiotic-free medium and then incubated in medium containing a single antibiotic (0 to 512 μg/ml). After incubation, the cells were challenged with Staphylococcus aureus ocular isolates, without antibiotics added to the culture medium. Epithelial cell layer integrity was assessed by gentian violet staining, and the minimum cell layer protective concentration (MCPC) of an antibiotic sufficient to protect the mammalian cells from S. aureus was determined. Staining was also quantified and analyzed. Bacterial viability was determined by culture turbidity and growth on agar plates. Preincubation of Chang and human corneal limbal epithelial cells with AZM, ERY, and TET at ≥64 μg/ml provided protection against AZM-susceptible S. aureus strains, with increasing protection at higher concentrations. TET toxicity was demonstrated at >64 μg/ml, whereas AZM displayed toxicity to one cell line at 512 μg/ml. BAC failed to show consistent protection at any dose, despite bacterial susceptibility to BAC as determined by traditional antibiotic susceptibility testing. A range of antibiotic effectiveness was displayed in this cell association assay, providing data that may be considered in addition to traditional testing when determining therapeutic dosing regimens. PMID:21628536

  1. Bacterial biofilm mechanical properties persist upon antibiotic treatment and survive cell death

    NASA Astrophysics Data System (ADS)

    Zrelli, K.; Galy, O.; Latour-Lambert, P.; Kirwan, L.; Ghigo, J. M.; Beloin, C.; Henry, N.

    2013-12-01

    Bacteria living on surfaces form heterogeneous three-dimensional consortia known as biofilms, where they exhibit many specific properties one of which is an increased tolerance to antibiotics. Biofilms are maintained by a polymeric network and display physical properties similar to that of complex fluids. In this work, we address the question of the impact of antibiotic treatment on the physical properties of biofilms based on recently developed tools enabling the in situ mapping of biofilm local mechanical properties at the micron scale. This approach takes into account the material heterogeneity and reveals the spatial distribution of all the small changes that may occur in the structure. With an Escherichia coli biofilm, we demonstrate using in situ fluorescent labeling that the two antibiotics ofloxacin and ticarcillin—targeting DNA replication and membrane assembly, respectively—induced no detectable alteration of the biofilm mechanical properties while they killed the vast majority of the cells. In parallel, we show that a proteolytic enzyme that cleaves extracellular proteins into short peptides, but does not alter bacterial viability in the biofilm, clearly affects the mechanical properties of the biofilm structure, inducing a significant increase of the material compliance. We conclude that conventional biofilm control strategy relying on the use of biocides targeting cells is missing a key target since biofilm structural integrity is preserved. This is expected to efficiently promote biofilm resilience, especially in the presence of persister cells. In contrast, the targeting of polymer network cross-links—among which extracellular proteins emerge as major players—offers a promising route for the development of rational multi-target strategies to fight against biofilms.

  2. Human homologues of a Borrelia T cell epitope associated with antibiotic-refractory Lyme arthritis.

    PubMed

    Drouin, Elise E; Glickstein, Lisa; Kwok, William W; Nepom, Gerald T; Steere, Allen C

    2008-01-01

    Antibiotic-refractory Lyme arthritis, which may result from infection-induced autoimmunity, is associated with HLA-DR molecules that bind an epitope of Borrelia burgdorferi (Bb) outer-surface protein A (OspA(165-173)) and with T cell reactivity with this epitope. One potential mechanism to explain these associations is molecular mimicry between OspA(165-173) and a self-peptide. Here, we searched the published human genome for peptides with sequence homology with OspA(165-173). The two peptides identified with the greatest sequence homology with the OspA epitope were MAWD-BP(276-288), which had identity at eight of the nine core amino acid residues, and T-span7(58-70), which had identity at six residues. MAWD-BP mRNA was expressed by synoviocytes, while T-span7 mRNA was not. However, neither peptide bound all of the HLA-DR molecules associated with antibiotic-refractory Lyme arthritis. Among 11 patients, 9 had T cell reactivity with OspA(161-170), 6 had responses to MAWD-BP(276-288), and 3 had reactivity with T-span7(58-70), but reactivity with the self-peptides was lower than that induced by the spirochetal epitope. Thus, there remains an association between OspA(165-173) and antibiotic-refractory Lyme arthritis, and infection-induced autoimmunity is an attractive hypothesis to explain this outcome. However, molecular mimicry due to sequence homology between OspA(165-173) and a human peptide seems unlikely to be the critical mechanism.

  3. Human Homologues of a Borrelia T cell Epitope Associated with Antibiotic-Refractory Lyme Arthritis

    PubMed Central

    Drouin, Elise E.; Glickstein, Lisa; Kwok, William W.; Nepom, Gerald T.; Steere, Allen C.

    2007-01-01

    Antibiotic-refractory Lyme arthritis, which may result from infection-induced autoimmunity, is associated with HLA-DR molecules that bind an epitope of Borrelia burgdorferi (Bb) outer-surface protein A (OspA165−173) and with T cell reactivity with this epitope. One potential mechanism to explain these associations is molecular mimicry between OspA165−173 and a self-peptide. Here, we searched the published human genome for peptides with sequence homology with OspA165−173. The two peptides identified with the greatest sequence homology with the OspA epitope were MAWD-BP276−288, which had identity at eight of the nine core amino acid residues, and T-span758−70, which had identity at six residues. MAWD-BP mRNA was expressed by synoviocytes, while T-span7 mRNA was not. However, neither peptide bound all of the HLA-DR molecules associated with antibiotic-refractory Lyme arthritis. Among 11 patients, nine had T cell reactivity with OspA161−170, six had responses to MAWD-BP276−288, and three had reactivity with T-span758−70, but reactivity with the self-peptides was lower than that induced by the spirochetal epitope. Thus, there remains an association between OspA165−173 and antibiotic-refractory Lyme arthritis, and infection-induced autoimmunity is an attractive hypothesis to explain this outcome. However, molecular mimicry due to sequence homology between OspA165−173 and a human peptide seems unlikely to be the critical mechanism. PMID:17555819

  4. Antibiotic Resistance

    MedlinePlus

    ... lives. But there is a growing problem of antibiotic resistance. It happens when bacteria change and become able ... resistant to several common antibiotics. To help prevent antibiotic resistance Don't use antibiotics for viruses like colds ...

  5. Effect of antibiotics against Mycoplasma sp. on human embryonic stem cells undifferentiated status, pluripotency, cell viability and growth.

    PubMed

    Romorini, Leonardo; Riva, Diego Ariel; Blüguermann, Carolina; Videla Richardson, Guillermo Agustin; Scassa, Maria Elida; Sevlever, Gustavo Emilio; Miriuka, Santiago Gabriel

    2013-01-01

    Human embryonic stem cells (hESCs) are self-renewing pluripotent cells that can differentiate into specialized cells and hold great promise as models for human development and disease studies, cell-replacement therapies, drug discovery and in vitro cytotoxicity tests. The culture and differentiation of these cells are both complex and expensive, so it is essential to extreme aseptic conditions. hESCs are susceptible to Mycoplasma sp. infection, which is hard to detect and alters stem cell-associated properties. The purpose of this work was to evaluate the efficacy and cytotoxic effect of Plasmocin(TM) and ciprofloxacin (specific antibiotics used for Mycoplasma sp. eradication) on hESCs. Mycoplasma sp. infected HUES-5 884 (H5 884, stable hESCs H5-brachyury promoter-GFP line) cells were effectively cured with a 14 days Plasmocin(TM) 25 µg/ml treatment (curative treatment) while maintaining stemness characteristic features. Furthermore, cured H5 884 cells exhibit the same karyotype as the parental H5 line and expressed GFP, through up-regulation of brachyury promoter, at day 4 of differentiation onset. Moreover, H5 cells treated with ciprofloxacin 10 µg/ml for 14 days (mimic of curative treatment) and H5 and WA09 (H9) hESCs treated with Plasmocin(TM) 5 µg/ml (prophylactic treatment) for 5 passages retained hESCs features, as judged by the expression of stemness-related genes (TRA1-60, TRA1-81, SSEA-4, Oct-4, Nanog) at mRNA and protein levels. In addition, the presence of specific markers of the three germ layers (brachyury, Nkx2.5 and cTnT: mesoderm; AFP: endoderm; nestin and Pax-6: ectoderm) was verified in in vitro differentiated antibiotic-treated hESCs. In conclusion, we found that Plasmocin(TM) and ciprofloxacin do not affect hESCs stemness and pluripotency nor cell viability. However, curative treatments slightly diminished cell growth rate. This cytotoxic effect was reversible as cells regained normal growth rate upon antibiotic withdrawal.

  6. Antibiotic Susceptibility of Biofilm Cells and Molecular Characterisation of Staphylococcus hominis Isolates from Blood

    PubMed Central

    Mendoza-Olazarán, Soraya; Morfín-Otero, Rayo; Villarreal-Treviño, Licet; Rodríguez-Noriega, Eduardo; Llaca-Díaz, Jorge; Camacho-Ortiz, Adrián; González, Gloria M.; Casillas-Vega, Néstor; Garza-González, Elvira

    2015-01-01

    Objectives We aimed to characterise the staphylococcal cassette chromosome mec (SCCmec) type, genetic relatedness, biofilm formation and composition, icaADBC genes detection, icaD expression, and antibiotic susceptibility of planktonic and biofilm cells of Staphylococcus hominis isolates from blood. Methods The study included 67 S. hominis blood isolates. Methicillin resistance was evaluated with the cefoxitin disk test. mecA gene and SCCmec were detected by multiplex PCR. Genetic relatedness was determined by pulsed-field gel electrophoresis. Biofilm formation and composition were evaluated by staining with crystal violet and by detachment assay, respectively; and the biofilm index (BI) was determined. Detection and expression of icaADBC genes were performed by multiplex PCR and real-time PCR, respectively. Antibiotic susceptibilities of planktonic cells (minimum inhibitory concentration, MIC) and biofilm cells (minimum biofilm eradication concentration, MBEC) were determined by the broth dilution method. Results Eighty-five percent (57/67) of isolates were methicillin resistant and mecA positive. Of the mecA-positive isolates, 66.7% (38/57) carried a new putative SCCmec type. Four clones were detected, with two to five isolates each. Among all isolates, 91% (61/67) were categorised as strong biofilm producers. Biofilm biomass composition was heterogeneous (polysaccharides, proteins and DNA). All isolates presented the icaD gene, and 6.66% (1/15) isolates expressed icaD. This isolate presented the five genes of ica operon. Higher BI and MBEC values than the MIC values were observed for amikacin, vancomycin, linezolid, oxacillin, ciprofloxacin, and chloramphenicol. Conclusions S. hominis isolates were highly resistant to methicillin and other antimicrobials. Most of the detected SCCmec types were different than those described for S. aureus. Isolates indicated low clonality. The results indicate that S. hominis is a strong biofilm producer with an extracellular

  7. Searching for Borrelial T cell Epitopes Associated with Antibiotic-Refractory Lyme Arthritis

    PubMed Central

    Drouin, Elise E.; Glickstein, Lisa; Kwok, William W.; Nepom, Gerald T.; Steere, Allen C.

    2008-01-01

    Antibiotic-refractory Lyme arthritis is believed to result from an infection-induced autoimmune response triggered by the spirochete Borrelia burgdorferi (Bb). Disease susceptibility is associated with the HLA alleles DRB1*0101, 0401, 0402, 0404, 0405 and DRB5*0101, and all these MHC molecules bind the Bb epitope OspA163-175. However, not all patients have a proliferative response to this epitope. To identify other possible Bb epitopes involved in this disease process, the algorithm TEPITOPE was used to scan 17 immunogenetic Bb proteins for potential T cell epitopes with a refractory arthritis-associated MHC binding profile, and the Bb proteome was searched for peptides with sequence homology to OspA165-173. Sixteen promising T epitopes were identified and their MHC binding profiles to 13 MHC molecules were verified using in vitro MHC/peptide binding assays. One peptide, BBK32392-404, had a strong refractory-arthritis associated MHC binding profile, and another GK297-306 shared sequence homology to OspA165-173. However, patient cells did not proliferate in response to either peptide making it highly unlikely they were involved in a refractory course. A comparison of the in silico and in vitro results revealed that TEPITOPE correctly predicted 74% of the in vitro binding peptides, but it incorrectly predicted that 44% of the in vitrononbinding peptides would bind. For a particular MHC molecule, concordance between the in silico and in vitro results varied anywhere between 33% and 100%. Therefore, while additional Bb epitopes may be involved in the development of antibiotic-refractory Lyme arthritis, recognition of OspA163-175 remains the only known Bb epitope associated with this disease. PMID:18191206

  8. Searching for borrelial T cell epitopes associated with antibiotic-refractory Lyme arthritis.

    PubMed

    Drouin, Elise E; Glickstein, Lisa; Kwok, William W; Nepom, Gerald T; Steere, Allen C

    2008-04-01

    Antibiotic-refractory Lyme arthritis is believed to result from an infection-induced autoimmune response triggered by the spirochete Borrelia burgdorferi (Bb). Disease susceptibility is associated with the HLA alleles DRB1*0101, 0401, 0402, 0404, 0405 and DRB5*0101, and all these MHC molecules bind the Bb epitope OspA(163-175.) However, not all patients have a proliferative response to this epitope. To identify other possible Bb epitopes involved in this disease process, the algorithm TEPITOPE was used to scan 17 immunogenic Bb proteins for potential T cell epitopes with a refractory arthritis-associated MHC binding profile, and the Bb proteome was searched for peptides with sequence homology to OspA(165-173). Sixteen promising T epitopes were identified and their MHC binding profiles to 13 MHC molecules were verified using in vitro MHC/peptide binding assays. One peptide, BBK32(392-404), had a strong refractory arthritis-associated MHC binding profile, and another GK(297-306) shared sequence homology to OspA(165-173). However, patient cells did not proliferate in response to either peptide making it highly unlikely they were involved in a refractory course. A comparison of the in silico and in vitro results revealed that TEPITOPE correctly predicted 74% of the in vitro binding peptides, but it incorrectly predicted that 44% of the in vitrononbinding peptides would bind. For a particular MHC molecule, concordance between the in silico and in vitro results varied anywhere between 33% and 100%. Therefore, while additional Bb epitopes may be involved in the development of antibiotic-refractory Lyme arthritis, recognition of OspA(163-175) remains the only known Bb epitope associated with this disease course.

  9. Interference of bacterial cell-to-cell communication: a new concept of antimicrobial chemotherapy breaks antibiotic resistance

    PubMed Central

    Hirakawa, Hidetada; Tomita, Haruyoshi

    2013-01-01

    Bacteria use a cell-to-cell communication activity termed “quorum sensing” to coordinate group behaviors in a cell density dependent manner. Quorum sensing influences the expression profile of diverse genes, including antibiotic tolerance and virulence determinants, via specific chemical compounds called “autoinducers”. During quorum sensing, Gram-negative bacteria typically use an acylated homoserine lactone (AHL) called autoinducer 1. Since the first discovery of quorum sensing in a marine bacterium, it has been recognized that more than 100 species possess this mechanism of cell-to-cell communication. In addition to being of interest from a biological standpoint, quorum sensing is a potential target for antimicrobial chemotherapy. This unique concept of antimicrobial control relies on reducing the burden of virulence rather than killing the bacteria. It is believed that this approach will not only suppress the development of antibiotic resistance, but will also improve the treatment of refractory infections triggered by multi-drug resistant pathogens. In this paper, we review and track recent progress in studies on AHL inhibitors/modulators from a biological standpoint. It has been discovered that both natural and synthetic compounds can disrupt quorum sensing by a variety of means, such as jamming signal transduction, inhibition of signal production and break-down and trapping of signal compounds. We also focus on the regulatory elements that attenuate quorum sensing activities and discuss their unique properties. Understanding the biological roles of regulatory elements might be useful in developing inhibitor applications and understanding how quorum sensing is controlled. PMID:23720655

  10. Antibiotic Resistance

    MedlinePlus

    ... For Consumers Consumer Information by Audience For Women Antibiotic Resistance Share Tweet Linkedin Pin it More sharing options ... these products really help. To Learn More about Antibiotic Resistance Get Smart About Antibiotics (Video) Fact Sheets and ...

  11. Thermodynamic analysis of the interaction of the antibiotic teicoplanin and its aglycone with cell-wall peptides.

    PubMed Central

    Arriaga, P; Laynez, J; Menendez, M; Cañada, J; Garcia-Blanco, F

    1990-01-01

    The thermodynamics of the interaction of the glycopeptidic antibiotic teicoplanin and its peptidic moiety with analogues of bacterial cell-wall peptides were studied by means of calorimetric and spectrophotometric techniques. The analysis of the thermodynamic data has allowed us to evaluate the contributions of the different peptide groups to the binding process. The nature of the primary binding forces is also discussed for each interacting group, on the basis of their enthalpic and entropic contribution and in connection with the detailed structural information available for these antibiotics from n.m.r. data. Similar analyses for the case of vancomycin and ristocetin are also reported. PMID:2137332

  12. Side effects of antibiotics during bacterial infection: mitochondria, the main target in host cell.

    PubMed

    Singh, Rochika; Sripada, Lakshmi; Singh, Rajesh

    2014-05-01

    Antibiotics are frontline therapy against microbial infectious diseases. Many antibiotics are known to cause several side effects in humans. Ribosomal RNA (rRNA) is the main target of antibiotics that inhibit protein synthesis. According to the endosymbiont theory, mitochondrion is of bacterial origin and their molecular and structural components of the protein expression system are almost similar. It has been observed that the rate of mutations in mitochondrial rRNA is higher as compared to that of nuclear rRNA. The presence of these mutations may mimic prokaryotic rRNA structure and bind to antibiotics targeted to ribosomes of bacteria. Mitochondrial functions are compromised hence may be one of the major causes of side effects observed during antibiotic therapy. The current review had summarized the studies on the role of antibiotics on mitochondrial functions and its relevance to the observed side effects in physiological and pathological conditions.

  13. Self-enhanced targeted delivery of a cell wall- and membrane-active antibiotics, daptomycin, against staphylococcal pneumonia.

    PubMed

    Jiang, Hong; Xiong, Meimei; Bi, Qiuyan; Wang, Ying; Li, Chong

    2016-07-01

    Considering that some antibacterial agents can identify the outer structure of pathogens like cell wall and/or cell membrane, we explored a self-enhanced targeted delivery strategy by which a small amount of the antibiotic molecules were modified on the surface of carriers as targeting ligands of certain bacteria while more antibiotic molecules were loaded inside the carriers, and thus has the potential to improve the drug concentration at the infection site, enhance efficacy and reduce potential toxicity. In this study, a novel targeted delivery system against methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was constructed with daptomycin, a lipopeptide antibiotic, which can bind to the cell wall of S. aureus via its hydrophobic tail. Daptomycin was conjugated with N-hydroxysuccinimidyl-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine to synthesize a targeting compound (Dapt-PEG-DSPE) which could be anchored on the surface of liposomes, while additional daptomycin molecules were encapsulated inside the liposomes. These daptomycin-modified, daptomycin-loaded liposomes (DPD-L[D]) showed specific binding to MRSA as detected by flow cytometry and good targeting capabilities in vivo to MRSA-infected lungs in a pneumonia model. DPD-L[D] exhibited more favorable antibacterial efficacy against MRSA than conventional PEGylated liposomal daptomycin both in vitro and in vivo. Our study demonstrates that daptomycin-modified liposomes can enhance MRSA-targeted delivery of encapsulated antibiotic, suggesting a novel drug delivery approach for existing antimicrobial agents. PMID:27471672

  14. The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets.

    PubMed

    Liu, Yao; Breukink, Eefjan

    2016-01-01

    Peptidoglycan is the major component of the cell envelope of virtually all bacteria. It has structural roles and acts as a selective sieve for molecules from the outer environment. Peptidoglycan synthesis is therefore one of the most important biogenesis pathways in bacteria and has been studied extensively over the last twenty years. The pathway starts in the cytoplasm, continues in the cytoplasmic membrane and finishes in the periplasmic space, where the precursor is polymerized into the peptidoglycan layer. A number of proteins involved in this pathway, such as the Mur enzymes and the penicillin binding proteins (PBPs), have been studied and regarded as good targets for antibiotics. The present review focuses on the membrane steps of peptidoglycan synthesis that involve two enzymes, MraY and MurG, the inhibitors of these enzymes and the inhibition mechanisms. We also discuss the challenges of targeting these two cytoplasmic membrane (associated) proteins in bacterial cells and the perspectives on how to overcome the issues. PMID:27571111

  15. The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets

    PubMed Central

    Liu, Yao; Breukink, Eefjan

    2016-01-01

    Peptidoglycan is the major component of the cell envelope of virtually all bacteria. It has structural roles and acts as a selective sieve for molecules from the outer environment. Peptidoglycan synthesis is therefore one of the most important biogenesis pathways in bacteria and has been studied extensively over the last twenty years. The pathway starts in the cytoplasm, continues in the cytoplasmic membrane and finishes in the periplasmic space, where the precursor is polymerized into the peptidoglycan layer. A number of proteins involved in this pathway, such as the Mur enzymes and the penicillin binding proteins (PBPs), have been studied and regarded as good targets for antibiotics. The present review focuses on the membrane steps of peptidoglycan synthesis that involve two enzymes, MraY and MurG, the inhibitors of these enzymes and the inhibition mechanisms. We also discuss the challenges of targeting these two cytoplasmic membrane (associated) proteins in bacterial cells and the perspectives on how to overcome the issues. PMID:27571111

  16. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells

    SciTech Connect

    Tang, Chunling; Yang, Liqun; Jiang, Xiaolan; Xu, Chuan; Wang, Mei; Wang, Qinrui; Zhou, Zhansong; Xiang, Zhonghuai; Cui, Hongjuan

    2014-03-28

    Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cell proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer.

  17. Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against Mycobacterium via altering the cell wall permeability.

    PubMed

    Li, Qiming; Zhou, Mingliang; Fan, Xiangyu; Yan, Jianlong; Li, Weimin; Xie, Jianping

    2016-01-01

    M. tuberculosis is intrinsically tolerant to many antibiotics largely due to the imperviousness of its unusual mycolic acid-containing cell wall to most antimicrobials. The emergence and increasingly widespread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) revitalized keen interest in phage-inspired therapy. SWU1gp39 is a novel gene from mycobacteriophage SWU1 with unknown function. SWU1gp39 expressed in M. smegmatis conferred the host cell increased susceptibility to multiple antibiotics, including isoniazid, erythromycin, norfloxacin, ampicillin, ciprofloxacin, ofloxacin, rifampicin and vancomycin, and multiple environment stresses such as H2O2, heat shock, low pH and SDS. By using EtBr/Nile red uptake assays, WT-pAL-gp39 strain showed higher cell wall permeability than control strain WT-pAL. Moreover, the WT-pAL-gp39 strain produced more reactive oxygen species and reduced NAD(+)/NADH ratio. RNA-Seq transcriptomes of the WT-pAL-gp39 and WT-pAL revealed that the transcription of 867 genes was differentially regulated, including genes associated with lipid metabolism. Taken together, our results implicated that SWU1gp39, a novel gene from mycobacteriophage, disrupted the lipid metabolism of host and increased cell wall permeability, ultimately potentiated the efficacy of multiple antibiotics and stresses against mycobacteria. PMID:27350398

  18. Mycobacteriophage SWU1 gp39 can potentiate multiple antibiotics against Mycobacterium via altering the cell wall permeability

    PubMed Central

    Li, Qiming; Zhou, Mingliang; Fan, Xiangyu; Yan, Jianlong; Li, Weimin; Xie, Jianping

    2016-01-01

    M. tuberculosis is intrinsically tolerant to many antibiotics largely due to the imperviousness of its unusual mycolic acid-containing cell wall to most antimicrobials. The emergence and increasingly widespread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) revitalized keen interest in phage-inspired therapy. SWU1gp39 is a novel gene from mycobacteriophage SWU1 with unknown function. SWU1gp39 expressed in M. smegmatis conferred the host cell increased susceptibility to multiple antibiotics, including isoniazid, erythromycin, norfloxacin, ampicillin, ciprofloxacin, ofloxacin, rifampicin and vancomycin, and multiple environment stresses such as H2O2, heat shock, low pH and SDS. By using EtBr/Nile red uptake assays, WT-pAL-gp39 strain showed higher cell wall permeability than control strain WT-pAL. Moreover, the WT-pAL-gp39 strain produced more reactive oxygen species and reduced NAD+/NADH ratio. RNA-Seq transcriptomes of the WT-pAL-gp39 and WT-pAL revealed that the transcription of 867 genes was differentially regulated, including genes associated with lipid metabolism. Taken together, our results implicated that SWU1gp39, a novel gene from mycobacteriophage, disrupted the lipid metabolism of host and increased cell wall permeability, ultimately potentiated the efficacy of multiple antibiotics and stresses against mycobacteria. PMID:27350398

  19. Effect of UV irradiation and magnetic field on immunometabolic effects of antibiotics immobilized in cell carriers.

    PubMed

    Lazarev, A I; Siplivyi, G V; Kukureka, A V; Siplivaya, L E

    2008-06-01

    The effects of UV and magnetic radiation on the immunometabolic activity of ampicillin and cephazolin immobilized in erythrocytic and leukocytic carriers were studied in intact Wistar rats and animals infected with staphylococci. Erythrocytic and leukocytic carriers with antibiotics were obtained. Injection of free antibiotics stimulated the immunosuppressive, pro-oxidant, and hepatotoxic effects, associated with staphylococcal infection. Treatment with antibiotics in erythrocytic and leukocytic carriers stimulated (to different degrees) the activity of the immune system and stabilized the parameters of LPO, antioxidant defense, cytolysis, and cholestasis. Ultraviolet irradiation and magnetic field modified (to different measures) the immunometabolic effects of ampicillin and cephazolin, immobilized in erythrocytic and leukocytic carriers, in animals with staphylococcal infection.

  20. Biotic acts of antibiotics

    PubMed Central

    Aminov, Rustam I.

    2013-01-01

    Biological functions of antibiotics are not limited to killing. The most likely function of antibiotics in natural microbial ecosystems is signaling. Does this signaling function of antibiotics also extend to the eukaryotic – in particular mammalian – cells? In this review, the host modulating properties of three classes of antibiotics (macrolides, tetracyclines, and β-lactams) will be briefly discussed. Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use. This use, however, should not compromise the primary function antibiotics are used for. The biological background for this inter-kingdom signaling is also discussed. PMID:23966991

  1. Dysregulation of CD4+CD25hi+ T cells in the synovial fluid of patients with antibiotic-refractory Lyme arthritis

    PubMed Central

    Vudattu, Nalini K.; Strle, Klemen; Steere, Allen C.; Drouin, Elise E.

    2013-01-01

    Objective To explore the role of immune dysregulation in antibiotic-refractory Lyme arthritis, the phenotype, frequency and function of CD4+ Teff and Treg cells were compared in patients with antibiotic-responsive or antibiotic-refractory arthritis. In the latter condition, infection-induced autoimmunity is thought to have a pathogenic role. Methods Matched peripheral blood (PB) and synovial fluid (SF) samples from 15 patients with antibiotic-responsive arthritis were compared with those from 16 patients with antibiotic-refractory arthritis using flow cytometry, suppression and cytokine assays. Results Critical differences between the 2 patient groups were found in the SF CD4+CD25hi+ populations, a subset of cells usually composed of FOXP3-positive Treg cells. In patients with antibiotic-refractory arthritis, this cell population often had fewer FOXP3-positive cells, and greater frequencies of FOXP3-negative (Teff) compared to patients with antibiotic-responsive arthritis. Moreover, in the refractory group, CD4+CD25hi+ cells had significantly greater expression of GITR and OX-40, two co-receptors that augment T cell function. Suppression assays showed that CD4+CD25hi+ cells in patients with refractory arthritis did not effectively suppress proliferation of CD4+CD25− cells, or secretion of IFN-γ or TNF-α, whereas those from patients with responsive arthritis did. Finally, in the refractory group, higher ratios of CD25hi+FOXP3−/CD25hi+FOXP3+ cells correlated directly with longer post-treatment durations of arthritis. Conclusion Patients with antibiotic-refractory Lyme arthritis often had lower frequencies of Treg, higher expression of activation co-receptors, and less effective inhibition of pro-inflammatory cytokines. This suggests that immune responses in these patients were excessively amplified leading to immune dysregulation and refractory arthritis. PMID:23450683

  2. Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.

    PubMed

    Lamb, Rebecca; Ozsvari, Bela; Lisanti, Camilla L; Tanowitz, Herbert B; Howell, Anthony; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2015-03-10

    Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of "stemness", independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point - a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known "side-effect", which could be harnessed instead as a "therapeutic effect". Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent

  3. Antibodies to Endothelial Cell Growth Factor and Obliterative Microvascular Lesions in Synovia of Patients with Antibiotic-Refractory Lyme Arthritis

    PubMed Central

    Londoño, Diana; Cadavid, Diego; Drouin, Elise E.; Strle, Klemen; McHugh, Gail; Aversa, John; Steere, Allen C.

    2014-01-01

    Objective Endothelial cell growth factor (ECGF) was recently identified as the first autoantigen known to be a target of T and B cell responses in about 20% of patients with antibiotic-refractory Lyme arthritis. The goal of the current study was to look for a pathologic correlate between ECGF autoantibody responses and histologic findings in synovial tissue. Methods Synovial tissue was examined from 14 patients with antibiotic-refractory Lyme arthritis and 6 patients with other forms of chronic inflammatory arthritis, primarily rheumatoid arthritis. The tissue sections were subjected to chemical and immunostaining, and IgG antibody responses to ECGF were determined by ELISA. Each finding was ranked for statistical analysis. Results In each disease, synovial tissue showed synovial hypertrophy, vascular proliferation, immune cell infiltrates, and fibrosis. However, among the 14 patients with antibiotic-refractory arthritis, 8 (57%) had obliterative microvascular lesions in the tissue compared with none of 6 patients with other forms of chronic inflammatory arthritis (P=0.04). Among the patients with Lyme arthritis, 5 (36%) had autoantibody responses to ECGF, and all 5 had obliterative lesions compared with only 3 of 9 patients who lacked ECGF antibody responses (P=0.009). Moreover, the magnitude of ECGF antibody responses correlated directly with the extent of obliterative lesions (P=0.02) and with greater vascularity in the tissue (P=0.05). Conclusions The correlations of ECGF autoantibody reactivity with obliterative microvascular lesions imply that these autoantibodies may be involved in the obliterative process, suggesting that anti-ECGF antibodies have specific pathologic consequences in synovial tissue in patients with antibiotic-refractory Lyme arthritis. PMID:24623727

  4. Antibiotic Safety

    MedlinePlus

    ... specific to women Antibiotics can lead to vaginal yeast infections. This happens because antibiotics kill the normal bacteria in the vagina and this causes yeast to grow rapidly. Symptoms of a yeast infection ...

  5. Antibiotic Agents

    MedlinePlus

    ... Work Contact Us ABOUT THE ISSUE What is Antibiotic Resistance? General Background Science of Resistance Glossary References POLICY ... for Adaptation Genetics and Drug Resistance Reservoirs of Antibiotic Resistance Project (ROAR) INTERNATIONAL CHAPTERS APUA Chapter Network Africa ...

  6. Bacterial cheating limits antibiotic resistance

    NASA Astrophysics Data System (ADS)

    Xiao Chao, Hui; Yurtsev, Eugene; Datta, Manoshi; Artemova, Tanya; Gore, Jeff

    2012-02-01

    The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain---which does not contribute to breaking down the antibiotic---may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors.

  7. Dialysate White Blood Cell Change after Initial Antibiotic Treatment Represented the Patterns of Response in Peritoneal Dialysis-Related Peritonitis

    PubMed Central

    Chuengsaman, Piyatida

    2016-01-01

    Background. Patients with peritoneal dialysis-related peritonitis usually have different responses to initial antibiotic treatment. This study aimed to explore the patterns of response by using the changes of dialysate white blood cell count on the first five days of the initial antibiotic treatment. Materials and Methods. A retrospective cohort study was conducted. All peritoneal dialysis-related peritonitis episodes from January 2014 to December 2015 were reviewed. We categorized the patterns of antibiotic response into 3 groups: early response, delayed response, and failure group. The changes of dialysate white blood cell count for each pattern were determined by multilevel regression analysis. Results. There were 644 episodes in 455 patients: 378 (58.7%) of early response, 122 (18.9%) of delayed response, and 144 (22.3%) of failure episodes. The patterns of early, delayed, and failure groups were represented by the average rate reduction per day of dialysate WBC of 68.4%, 34.0%, and 14.2%, respectively (p value < 0.001 for all comparisons). Conclusion. Three patterns, which were categorized by types of responses, have variable rates of WBC declining. Clinicians should focus on the delayed response and failure patterns in order to make a decision whether to continue medical therapies or to aggressively remove the peritoneal catheter.

  8. Dialysate White Blood Cell Change after Initial Antibiotic Treatment Represented the Patterns of Response in Peritoneal Dialysis-Related Peritonitis.

    PubMed

    Tantiyavarong, Pichaya; Traitanon, Opas; Chuengsaman, Piyatida; Patumanond, Jayanton; Tasanarong, Adis

    2016-01-01

    Background. Patients with peritoneal dialysis-related peritonitis usually have different responses to initial antibiotic treatment. This study aimed to explore the patterns of response by using the changes of dialysate white blood cell count on the first five days of the initial antibiotic treatment. Materials and Methods. A retrospective cohort study was conducted. All peritoneal dialysis-related peritonitis episodes from January 2014 to December 2015 were reviewed. We categorized the patterns of antibiotic response into 3 groups: early response, delayed response, and failure group. The changes of dialysate white blood cell count for each pattern were determined by multilevel regression analysis. Results. There were 644 episodes in 455 patients: 378 (58.7%) of early response, 122 (18.9%) of delayed response, and 144 (22.3%) of failure episodes. The patterns of early, delayed, and failure groups were represented by the average rate reduction per day of dialysate WBC of 68.4%, 34.0%, and 14.2%, respectively (p value < 0.001 for all comparisons). Conclusion. Three patterns, which were categorized by types of responses, have variable rates of WBC declining. Clinicians should focus on the delayed response and failure patterns in order to make a decision whether to continue medical therapies or to aggressively remove the peritoneal catheter. PMID:27656294

  9. Dialysate White Blood Cell Change after Initial Antibiotic Treatment Represented the Patterns of Response in Peritoneal Dialysis-Related Peritonitis

    PubMed Central

    Chuengsaman, Piyatida

    2016-01-01

    Background. Patients with peritoneal dialysis-related peritonitis usually have different responses to initial antibiotic treatment. This study aimed to explore the patterns of response by using the changes of dialysate white blood cell count on the first five days of the initial antibiotic treatment. Materials and Methods. A retrospective cohort study was conducted. All peritoneal dialysis-related peritonitis episodes from January 2014 to December 2015 were reviewed. We categorized the patterns of antibiotic response into 3 groups: early response, delayed response, and failure group. The changes of dialysate white blood cell count for each pattern were determined by multilevel regression analysis. Results. There were 644 episodes in 455 patients: 378 (58.7%) of early response, 122 (18.9%) of delayed response, and 144 (22.3%) of failure episodes. The patterns of early, delayed, and failure groups were represented by the average rate reduction per day of dialysate WBC of 68.4%, 34.0%, and 14.2%, respectively (p value < 0.001 for all comparisons). Conclusion. Three patterns, which were categorized by types of responses, have variable rates of WBC declining. Clinicians should focus on the delayed response and failure patterns in order to make a decision whether to continue medical therapies or to aggressively remove the peritoneal catheter. PMID:27656294

  10. [Antibiotic Stewardship].

    PubMed

    Lanckohr, Christian; Ellger, Björn

    2016-02-01

    The adequate management of infections is an important task in critical care medicine which has an effect on patient outcome. As a result, the prevalence of antiinfective therapy is high in intensive care units. In the face of an unsettling development of worldwide microbial resistance, an optimization and reduction of antiinfective therapy is necessary. Antibiotic stewardship tries to improve antiinfective therapy with an interdisciplinary approach. One overall objective of antibiotic stewardship is the reduction of resistance induction in order to preserve the therapeutic efficiency of antibiotics. Intensive care units are important fields of action for antibiotic stewardship interventions. This article reviews available evidence and some practical aspects for antibiotic stewardship.

  11. The Bacterial Cell Wall in the Antibiotic Era: An Ontology in Transit Between Morphology and Metabolism, 1940s-1960s.

    PubMed

    Santesmases, María Jesús

    2016-02-01

    This essay details a historical crossroad in biochemistry and microbiology in which penicillin was a co-agent. I narrate the trajectory of the bacterial cell wall as the precise target for antibiotic action. As a strategic object of research, the bacterial cell wall remained at the core of experimental practices, scientific narratives and research funding appeals throughout the antibiotic era. The research laboratory was dedicated to the search for new antibiotics while remaining the site at which the mode of action of this new substance was investigated. This combination of circumstances made the bacterial wall an ontology in transit. As invisible as the bacterial wall was for clinical purposes, in the biological laboratory, cellular meaning in regard to the action of penicillin made the bacterial wall visible within both microbiology and biochemistry. As a border to be crossed, some components of the bacterial cell wall and the biochemical destruction produced by penicillin became known during the 1950s and 1960s. The cell wall was constructed piece by piece in a transatlantic circulation of methods, names, and images of the shape of the wall itself. From 1955 onwards, microbiologists and biochemists mobilized new names and associated conceptual meanings. The composition of this thin and rigid layer would account for its shape, growth and destruction. This paper presents a history of biochemical morphology: a chemistry of shape - the shape of bacteria, as provided by its wall - that accounted for biology, for life itself. While penicillin was being established as an industrially-manufactured object, it remained a scientific tool within the research laboratory, contributing to the circulation of further scientific objects.

  12. The Ribosome: The Cell's Protein-Synthesizing Machine and How Antibiotics Disrupt It

    SciTech Connect

    Venki Ramakrishnan

    2009-10-08

    Determining the structure of the ribosome has made it possible for Ramakrishnan and his colleagues to image antibiotics bound to the ribosome, leading to a better understanding of their action, which could help in the development of novel drugs. In his ta

  13. The Ribosome: The Cell's Protein-Synthesizing Machine and How Antibiotics Disrupt It

    ScienceCinema

    Venki Ramakrishnan

    2016-07-12

    Determining the structure of the ribosome has made it possible for Ramakrishnan and his colleagues to image antibiotics bound to the ribosome, leading to a better understanding of their action, which could help in the development of novel drugs. In his ta

  14. The multifaceted roles of antibiotics and antibiotic resistance in nature

    PubMed Central

    Sengupta, Saswati; Chattopadhyay, Madhab K.; Grossart, Hans-Peter

    2013-01-01

    Antibiotics are chemotherapeutic agents, which have been a very powerful tool in the clinical management of bacterial diseases since the 1940s. However, benefits offered by these magic bullets have been substantially lost in subsequent days following the widespread emergence and dissemination of antibiotic-resistant strains. While it is obvious that excessive and imprudent use of antibiotics significantly contributes to the emergence of resistant strains, antibiotic resistance is also observed in natural bacteria of remote places unlikely to be impacted by human intervention. Both antibiotic biosynthetic genes and resistance-conferring genes have been known to evolve billions of years ago, long before clinical use of antibiotics. Hence it appears that antibiotics and antibiotics resistance determinants have some other roles in nature, which often elude our attention because of overemphasis on the therapeutic importance of antibiotics and the crisis imposed by the antibiotic resistance in pathogens. In the natural milieu, antibiotics are often found to be present in sub-inhibitory concentrations acting as signaling molecules supporting the process of quorum sensing and biofilm formation. They also play an important role in the production of virulence factors and influence host–parasite interactions (e.g., phagocytosis, adherence to the target cell, and so on). The evolutionary and ecological aspects of antibiotics and antibiotic resistance in the naturally occurring microbial community are little understood. Therefore, the actual role of antibiotics in nature warrants in-depth investigations. Studies on such an intriguing behavior of the microorganisms promise insight into the intricacies of the microbial physiology and are likely to provide some lead in controlling the emergence and subsequent dissemination of antibiotic resistance. This article highlights some of the recent findings on the role of antibiotics and the genes that confer resistance to antibiotics

  15. Bacillus subtilis as a platform for molecular characterisation of regulatory mechanisms of Enterococcus faecalis resistance against cell wall antibiotics.

    PubMed

    Fang, Chong; Stiegeler, Emanuel; Cook, Gregory M; Mascher, Thorsten; Gebhard, Susanne

    2014-01-01

    To combat antibiotic resistance of Enterococcus faecalis, a better understanding of the molecular mechanisms, particularly of antibiotic detection, signal transduction and gene regulation is needed. Because molecular studies in this bacterium can be challenging, we aimed at exploiting the genetically highly tractable Gram-positive model organism Bacillus subtilis as a heterologous host. Two fundamentally different regulators of E. faecalis resistance against cell wall antibiotics, the bacitracin sensor BcrR and the vancomycin-sensing two-component system VanSB-VanRB, were produced in B. subtilis and their functions were monitored using target promoters fused to reporter genes (lacZ and luxABCDE). The bacitracin resistance system BcrR-BcrAB of E. faecalis was fully functional in B. subtilis, both regarding regulation of bcrAB expression and resistance mediated by the transporter BcrAB. Removal of intrinsic bacitracin resistance of B. subtilis increased the sensitivity of the system. The lacZ and luxABCDE reporters were found to both offer sensitive detection of promoter induction on solid media, which is useful for screening of large mutant libraries. The VanSB-VanRB system displayed a gradual dose-response behaviour to vancomycin, but only when produced at low levels in the cell. Taken together, our data show that B. subtilis is a well-suited host for the molecular characterization of regulatory systems controlling resistance against cell wall active compounds in E. faecalis. Importantly, B. subtilis facilitates the careful adjustment of expression levels and genetic background required for full functionality of the introduced regulators.

  16. An Inactivated Antibiotic-Exposed Whole-Cell Vaccine Enhances Bactericidal Activities Against Multidrug-Resistant Acinetobacter baumannii

    PubMed Central

    Shu, Meng-Hooi; MatRahim, NorAziyah; NorAmdan, NurAsyura; Pang, Sui-Ping; Hashim, Sharina H.; Phoon, Wai-Hong; AbuBakar, Sazaly

    2016-01-01

    Vaccination may be an alternative treatment for infection with multidrug-resistance (MDR) Acinetobacter baumannii. The study reported here evaluated the bactericidal antibody responses following immunization of mice using an inactivated whole-cell vaccine derived from antibiotic-exposed MDR A. baumannii (I-M28-47-114). Mice inoculated with I-M28-47 (non-antibiotic-exposed control) and I-M28-47-114 showed a high IgG antibody response by day 5 post-inoculation. Sera from mice inoculated with I-M28-47-114 collected on day 30 resulted in 80.7 ± 12.0% complement-mediated bacteriolysis in vitro of the test MDR A. baumannii treated with imipenem, which was a higher level of bacteriolysis over sera from mice inoculated with I-M28-47. Macrophage-like U937 cells eliminated 49.3 ± 11.6% of the test MDR A. baumannii treated with imipenem when opsonized with sera from mice inoculated with I-M28-47-114, which was a higher level of elimination than observed for test MDR A. baumannii opsonized with sera from mice inoculated with I-M28-47. These results suggest that vaccination with I-M28-47-114 stimulated antibody responses capable of mounting high bactericidal killing of MDR A. baumannii. Therefore, the inactivated antibiotic-exposed whole-cell vaccine (I-M28-47-114) has potential for development as a candidate vaccine for broad clearance and protection against MDR A. baumannii infections. PMID:26923424

  17. Reprogrammable microbial cell-based therapeutics against antibiotic-resistant bacteria.

    PubMed

    Hwang, In Young; Koh, Elvin; Kim, Hye Rim; Yew, Wen Shan; Chang, Matthew Wook

    2016-07-01

    The discovery of antimicrobial drugs and their subsequent use has offered an effective treatment option for bacterial infections, reducing morbidity and mortality over the past 60 years. However, the indiscriminate use of antimicrobials in the clinical, community and agricultural settings has resulted in selection for multidrug-resistant bacteria, which has led to the prediction of possible re-entrance to the pre-antibiotic era. The situation is further exacerbated by significantly reduced antimicrobial drug discovery efforts by large pharmaceutical companies, resulting in a steady decline in the number of new antimicrobial agents brought to the market in the past several decades. Consequently, there is a pressing need for new antimicrobial therapies that can be readily designed and implemented. Recently, it has become clear that the administration of broad-spectrum antibiotics can lead to collateral damage to the human commensal microbiota, which plays several key roles in host health. Advances in genetic engineering have opened the possibility of reprogramming commensal bacteria that are in symbiotic existence throughout the human body to implement antimicrobial drugs with high versatility and efficacy against pathogenic bacteria. In this review, we discuss recent advances and potentialities of engineered bacteria in providing a novel antimicrobial strategy against antibiotic resistance. PMID:27449598

  18. Selection of antibiotic resistance at very low antibiotic concentrations.

    PubMed

    Sandegren, Linus

    2014-05-01

    Human use of antibiotics has driven the selective enrichment of pathogenic bacteria resistant to clinically used drugs. Traditionally, the selection of resistance has been considered to occur mainly at high, therapeutic levels of antibiotics, but we are now beginning to understand better the importance of selection of resistance at low levels of antibiotics. The concentration of an antibiotic varies in different body compartments during treatment, and low concentrations of antibiotics are found in sewage water, soils, and many water environments due to natural production and contamination from human activities. Selection of resistance at non-lethal antibiotic concentrations (below the wild-type minimum inhibitory concentration) occurs due to differences in growth rate at the particular antibiotic concentration between cells with different tolerance levels to the antibiotic. The minimum selective concentration for a particular antibiotic is reached when its reducing effect on growth of the susceptible strain balances the reducing effect (fitness cost) of the resistance determinant in the resistant strain. Recent studies have shown that resistant bacteria can be selected at concentrations several hundred-fold below the lethal concentrations for susceptible cells. Resistant mutants selected at low antibiotic concentrations are generally more fit than those selected at high concentrations but can still be highly resistant. The characteristics of selection at low antibiotic concentrations, the potential clinical problems of this mode of selection, and potential solutions will be discussed.

  19. Studies of Antibiotic Resistance of Beta-Lactamase Bacteria under Different Nutrition Limitations at the Single-Cell Level

    PubMed Central

    Wang, Ying; Ran, Min; Wang, Jun; Ouyang, Qi; Luo, Chunxiong

    2015-01-01

    Drug resistance involves many biological processes, including cell growth, cell communication, and cell cooperation. In the last few decades, bacterial drug resistance studies have made substantial progress. However, a major limitation of the traditional resistance study still exists: most of the studies have concentrated on the average behavior of enormous amounts of cells rather than surveying single cells with different phenotypes or genotypes. Here, we report our study of beta-lactamase bacterial drug resistance in a well-designed microfluidic device, which allows us to conduct more controllable experiments, such as controlling the nutrient concentration, switching the culture media, performing parallel experiments, observing single cells, and acquiring time-lapse images. By using GFP as a beta-lactamase indicator and acquiring time-lapse images at the single-cell level, we observed correlations between the bacterial heterogeneous phenotypes and their behavior in different culture media. The feedback loop between the growth rate and the beta-lactamase production suggests that the beta-lactamase bacteria are more resistant in a rich medium than in a relatively poor medium. In the poorest medium, the proportion of dormant cells may increase, which causes a lower death rate in the same generation. Our work may contribute to assaying the antibiotic resistance of pathogenic bacteria in heterogeneous complex media. PMID:25993008

  20. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells

    PubMed Central

    Deng, Youlin; Zhang, Junhui; Wang, Zhongliang; Yan, Zhengjian; Qiao, Min; Ye, Jixing; Wei, Qiang; Wang, Jing; Wang, Xin; Zhao, Lianggong; Lu, Shun; Tang, Shengli; Mohammed, Maryam K.; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Zou, Yulong; Liao, Junyi; Qi, Hongbo; Haydon, Rex C.; Luu, Hue H.; He, Tong-Chuan; Tang, Liangdan

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12–24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID:26639992

  1. Antibiotic monensin synergizes with EGFR inhibitors and oxaliplatin to suppress the proliferation of human ovarian cancer cells.

    PubMed

    Deng, Youlin; Zhang, Junhui; Wang, Zhongliang; Yan, Zhengjian; Qiao, Min; Ye, Jixing; Wei, Qiang; Wang, Jing; Wang, Xin; Zhao, Lianggong; Lu, Shun; Tang, Shengli; Mohammed, Maryam K; Liu, Hao; Fan, Jiaming; Zhang, Fugui; Zou, Yulong; Liao, Junyi; Qi, Hongbo; Haydon, Rex C; Luu, Hue H; He, Tong-Chuan; Tang, Liangdan

    2015-01-01

    Ovarian cancer is the most lethal gynecologic malignancy with an overall cure rate of merely 30%. Most patients experience recurrence within 12-24 months of cure and die of progressively chemotherapy-resistant disease. Thus, more effective anti-ovarian cancer therapies are needed. Here, we investigate the possibility of repurposing antibiotic monensin as an anti-ovarian cancer agent. We demonstrate that monensin effectively inhibits cell proliferation, migration and cell cycle progression, and induces apoptosis of human ovarian cancer cells. Monensin suppresses multiple cancer-related pathways including Elk1/SRF, AP1, NFκB and STAT, and reduces EGFR expression in ovarian cancer cells. Monensin acts synergistically with EGFR inhibitors and oxaliplatin to inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Xenograft studies confirm that monensin effectively inhibits tumor growth by suppressing cell proliferation through targeting EGFR signaling. Our results suggest monensin may be repurposed as an anti-ovarian cancer agent although further preclinical and clinical studies are needed. PMID:26639992

  2. Antibacterial properties of cationic steroid antibiotics.

    PubMed

    Savage, Paul B; Li, Chunhong; Taotafa, Uale; Ding, Bangwei; Guan, Qunying

    2002-11-19

    Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activity. These compounds are comprised of steroids appended with amine groups arranged to yield facially amphiphilic morphology. Examples of these antibiotics are highly bactericidal, while related compounds effectively permeabilize the outer membranes of Gram-negative bacteria sensitizing these organisms to hydrophobic antibiotics. Cationic steroid antibiotics exhibit various levels of eukaryote vs. prokaryote cell selectivity, and cell selectivity can be increased via charge recognition of prokaryotic cells. Studies of the mechanism of action of these antibiotics suggest that they share mechanistic aspects with cationic peptide antibiotics. PMID:12445638

  3. Contribution of Resistance-Nodulation-Cell Division Efflux Systems to Antibiotic Resistance and Biofilm Formation in Acinetobacter baumannii

    PubMed Central

    Yoon, Eun-Jeong; Nait Chabane, Yassine; Goussard, Sylvie; Snesrud, Erik; Courvalin, Patrice; Dé, Emmanuelle

    2015-01-01

    ABSTRACT Acinetobacter baumannii is a nosocomial pathogen of increasing importance due to its multiple resistance to antibiotics and ability to survive in the hospital environment linked to its capacity to form biofilms. To fully characterize the contribution of AdeABC, AdeFGH, and AdeIJK resistance-nodulation-cell division (RND)-type efflux systems to acquired and intrinsic resistance, we constructed, from an entirely sequenced susceptible A. baumannii strain, a set of isogenic mutants overexpressing each system following introduction of a point mutation in their cognate regulator or a deletion for the pump by allelic replacement. Pairwise comparison of every derivative with the parental strain indicated that AdeABC and AdeFGH are tightly regulated and contribute to acquisition of antibiotic resistance when overproduced. AdeABC had a broad substrate range, including β-lactams, fluoroquinolones, tetracyclines-tigecycline, macrolides-lincosamides, and chloramphenicol, and conferred clinical resistance to aminoglycosides. Importantly, when combined with enzymatic resistance to carbapenems and aminoglycosides, this pump contributed in a synergistic fashion to the level of resistance of the host. In contrast, AdeIJK was expressed constitutively and was responsible for intrinsic resistance to the same major drug classes as AdeABC as well as antifolates and fusidic acid. Surprisingly, overproduction of AdeABC and AdeIJK altered bacterial membrane composition, resulting in decreased biofilm formation but not motility. Natural transformation and plasmid transfer were diminished in recipients overproducing AdeABC. It thus appears that alteration in the expression of efflux systems leads to multiple changes in the relationship between the host and its environment, in addition to antibiotic resistance. PMID:25805730

  4. Synergistic inhibition of angiogenesis and glioma cell-induced angiogenesis by the combination of temozolomide and enediyne antibiotic lidamycin

    PubMed Central

    Li, Xing-qi; Ouyang, Zhi-gang; Zhang, Sheng-hua; Liu, Hong; Shang, Yue; Li, Yi; Zhen, Yong-su

    2014-01-01

    Present work mainly evaluated the inhibitory effects of lidamycin (LDM), an enediyne antibiotic, on angiogenesis or glioma-induced angiogenesis in vitro and in vivo, especially its synergistic anti-angiogenesis with temozolomide (TMZ). LDM alone efficiently inhibited proliferations and induced apoptosis of rat brain microvessel endothelial cells (rBMEC). LDM also interrupted the tube formation of rat brain microvessel endothelial cells (rBMEC) and rat aortic ring spreading. The blockade of rBMEC invasion and C6 cell-induced rBMEC migration by LDM was associated with decrease of VEGF secretion in a co-culture system. TMZ dramatically potentiated the effects of LDM on anti-proliferation, apoptosis induction, and synergistically inhibited angiogenesis events. As determined by western blot and ELISA, the interaction of tumor cells and the rBMEC was markedly interrupted by LDM plus TMZ with synergistic regulations of VEGF induced angiogenesis signal pathway, tumor cell invasion/migration, and apoptosis signal pathway. Immunofluorohistochemistry of CD31 and VEGF showed that LDM plus TMZ resulted in synergistic decrease of microvessel density (MVD) and VEGF expression in human glioma U87 cell subcutaneous xenograft. This study indicates that the high efficacy of LDM and the synergistic effects of LDM plus TMZ against glioma are mediated, at least in part, by the potentiated anti-angiogenesis. PMID:24424202

  5. A new antitumor antibiotic, kazusamycin.

    PubMed

    Umezawa, I; Komiyama, K; Oka, H; Okada, K; Tomisaka, S; Miyano, T; Takano, S

    1984-07-01

    A new antibiotic kazusamycin, was isolated from the culture broth of Streptomyces sp. No. 81-484, which shows antitumor activity against experimental murine tumors. This antibiotic did not possess antibacterial activity against Gram-positive and Gram-negative bacteria, but showed strong cytotoxic activity against HeLa cells in vitro. The chemical and physico-chemical properties of kazusamycin suggest that the molecular formula of this antibiotic is C33H48O7 (MW 556). PMID:6432763

  6. Antibiotics Quiz

    MedlinePlus

    ... Viruses b) Bacteria c) Viruses and Bacteria 2. Bacteria are germs that cause colds and flu. a) ... The Flu c) Cold d) Strep Throat 4. Bacteria that cause infections can become resistant to antibiotics. ...

  7. Transport of the antitumor antibiotic Cl-920 into L1210 leukemia cells by the reduced folate carrier system.

    PubMed

    Fry, D W; Besserer, J A; Boritzki, T J

    1984-08-01

    Cl-920 is a structurally novel antitumor antibiotic which has activity against a wide spectrum of tumor cells in vitro and is curative in L1210 leukemia in vivo. Several lines of evidence indicate that this drug penetrates L1210 cells via the reduced folate carrier system. Reduced folates (100 microM) including leucovorin and 5-methyltetrahydrofolate completely protected L1210 cells from growth inhibition by Cl-920. Protective effects were not observed, however, with folic acid, a compound which is transported by a process distinct from that for reduced folates. Cl-920 was a potent inhibitor of methotrexate influx exhibiting a mixture of competitive and noncompetitive inhibition and having a Ki (slope) of 30.0 microM and a Ki (intercept) of 58.8 microM. The inhibition appeared to be irreversible since, after cells were preincubated with drug, the inhibitory effects persisted after cells were washed in drug-free media. The irreversibility could be eliminated, however, by dithiothreitol, suggesting that Cl-920 may interact with a thiol which is essential to this transport system. Cells made 71-fold resistant to Cl-920 by continuous exposure to increasing concentrations of this drug were 245-fold cross-resistant to methotrexate but were collaterally sensitive to the lipophilic antifolate trimetrexate and contained normal levels of dihydrofolate reductase. This mutant cell line had a severely impaired reduced folate carrier system exhibiting methotrexate influx rates of less than 1% of control cells. Finally, inhibition of methotrexate influx by a number of Cl-920 analogues showed that the intact lactone ring and the presence of the phosphate ester were required for maximum interaction with the carrier system and that the degree of inhibition correlated with relative antitumor potency. These observations are compatible with the concept that Cl-920 utilizes the folate carrier system and could be of fundamental importance for understanding the cytotoxicity and

  8. Multifunctional nanocrystalline calcium phosphates loaded with Tetracycline antibiotic combined with human adipose derived mesenchymal stromal stem cells (hASCs).

    PubMed

    Marycz, K; Pazik, R; Zawisza, K; Wiglusz, K; Maredziak, M; Sobierajska, P; Wiglusz, R J

    2016-12-01

    Osteoconductive drug delivery system composed of nanocrystalline calcium phosphates (Ca10(PO4)6(OH)2/β-Ca3(PO4)2) co-doped with Yb(3+)/Er(3+) ions loaded with Tetracycline antibiotic (TC) was developed. Their effect on human adipose derived mesenchymal stromal stem cells (hASCs) as a potential reconstructive biomaterial for bone tissue regeneration was studied. The XRD and TEM measurements were used in order to determine the crystal structure and morphology of the final products. The characteristics of nanocomposites with the TC and hASCs as potential regenerative materials as well as the antimicrobial activity of the nanoparticles against: Staphylococcus aureus ATCC 25923 as a model of the Gram-positive bacteria, Escherichia coli ATCC 8739 of the Gram-negative bacteria, were shown. These combinations can be a promising material for theranostic due to its regenerative, antimicrobial and fluorescent properties. PMID:27612684

  9. Molecular responses to photogenotoxic stress induced by the antibiotic lomefloxacin in human skin cells: from DNA damage to apoptosis.

    PubMed

    Marrot, Laurent; Belaïdi, Jean Phillipe; Jones, Christophe; Perez, Phillipe; Riou, Lydia; Sarasin, Alain; Meunier, Jean Roch

    2003-09-01

    Photo-unstable chemicals sometimes behave as phototoxins in skin, inducing untoward clinical side-effects when exposed to sunlight. Some drugs, such as psoralens or fluoroquinolones, can damage genomic DNA, thus increasing the risk of photocarcinogenesis. Here, lomefloxacin, an antibiotic from the fluoroquinolone family known to be involved in skin tumor development in photoexposed mice, was studied using normal human skin cells in culture: fibroblasts, keratinocytes, and Caucasian melanocytes. When treated cells were exposed to simulated solar ultraviolet A (320-400 nm), lomefloxacin induced damage such as strand breaks and pyrimidine dimers in genomic DNA. Lomefloxacin also triggered various stress responses: heme-oxygenase-1 expression in fibroblasts, changes in p53 status as shown by the accumulation of p53 and p21 proteins or the induction of MDM2 and GADD45 genes, and stimulation of melanogenesis by increasing the tyrosinase activity in melanocytes. Lomefloxacin could also lead to apoptosis in keratinocytes exposed to ultraviolet A: caspase-3 was activated and FAS-L gene was induced. Moreover, keratinocytes were shown to be the most sensitive cell type to lomefloxacin phototoxic effects, in spite of the well-established effectiveness of their antioxidant equipment. These data show that the phototoxicity of a given drug can be driven by different mechanisms and that its biologic impact varies according to cell type.

  10. Collective antibiotic tolerance: Mechanisms, dynamics, and intervention

    PubMed Central

    Meredith, Hannah R.; Srimani, Jaydeep K.; Lee, Anna J.; Lopatkin, Allison J.; You, Lingchong

    2016-01-01

    Bacteria have developed resistance against every antibiotic at an alarming rate, considering the timescale at which new antibiotics are developed. Thus, there is a critical need to use antibiotics more effectively, extend the shelf life of existing antibiotics, and minimize their side effects. This requires understanding the mechanisms underlying bacterial drug responses. Past studies have focused on survival in the presence of antibiotics by individual cells, as genetic mutants or persisters. In contrast, a population of bacterial cells can collectively survive antibiotic treatments lethal to individual cells. This tolerance can arise by diverse mechanisms, including resistance-conferring enzyme production, titration-mediated bistable growth inhibition, swarming, and inter-population interactions. These strategies can enable rapid population recovery after antibiotic treatment, and provide a time window for otherwise susceptible bacteria to acquire inheritable genetic resistance. Here, we emphasize the potential for targeting collective antibiotic tolerance behaviors as an antibacterial treatment strategy. PMID:25689336

  11. [14-O-hemiesters and 13-hydrazones of anthracyline antibiotics of the daunorubicin series. Synthesis and cytostatic activity with respect to tumor cells sensitive or resistant to doxorubicin].

    PubMed

    Povarov, L S; Leont'eva, O V; Bernaki, P D; Olsuf'eva, E N; Salimova, E I; Pera, P; Preobrazhenskaia, M N

    1995-12-01

    Doxorubicin and 14-hydroxycarminomycin 14-O-hemiadipates and 14-O-hemipimelates, synthesized from 14-bromo derivatives of daunorubicin and carminomycin and monosodium adipate and pimelate, were converted to the corresponding N-trifluoroacetylated compounds. 13-(4-Methylpiperazine-1-yl)imino derivatives of the anthracycline antibiotics were also obtained. The cytostatic activity of the compounds synthesized was studied using a panel of human and animal tumor cell lines sensitive or resistant to doxorubicin. N-Trifluoroacetylation of the antibiotics resulted in a decrease in the cytostatic activity. The activity of the water-soluble 13-(4-methylpiperazine-l-yl)imino derivatives is close to that of the corresponding parent antibiotics.

  12. Aerosolized Antibiotics.

    PubMed

    Restrepo, Marcos I; Keyt, Holly; Reyes, Luis F

    2015-06-01

    Administration of medications via aerosolization is potentially an ideal strategy to treat airway diseases. This delivery method ensures high concentrations of the medication in the targeted tissues, the airways, with generally lower systemic absorption and systemic adverse effects. Aerosolized antibiotics have been tested as treatment for bacterial infections in patients with cystic fibrosis (CF), non-CF bronchiectasis (NCFB), and ventilator-associated pneumonia (VAP). The most successful application of this to date is treatment of infections in patients with CF. It has been hypothesized that similar success would be seen in NCFB and in difficult-to-treat hospital-acquired infections such as VAP. This review summarizes the available evidence supporting the use of aerosolized antibiotics and addresses the specific considerations that clinicians should recognize when prescribing an aerosolized antibiotic for patients with CF, NCFB, and VAP.

  13. Antibiotic activity in space.

    PubMed

    Lapchine, L; Moatti, N; Gasset, G; Richoilley, G; Templier, J; Tixador, R

    1986-01-01

    Environmental factors in space exert an influence on the behaviour of bacteria, particularly on their sensitivity to antibiotics. Thus, G. Taylor and S. Zaloguev observed that bacterial samples collected on the crew during flight in the Apollo-Soyouz Test Project Mission presented higher antibiotic resistance than controls. This paper presents the results of two experiments performed in 1982 and 1985 (Cytos 2 during the French-Soviet Mission and "Antibio" in the Biorack programme of the European Space Agency). The results show an increase of antibiotic resistance in bacteria growth in flight and a modification in the structure of the cell wall. All these modifications are transitory. Two hypotheses are put forward to explain the phenomenon.

  14. Antibiotic activity in space.

    PubMed

    Lapchine, L; Moatti, N; Gasset, G; Richoilley, G; Templier, J; Tixador, R

    1986-01-01

    Environmental factors in space exert an influence on the behaviour of bacteria, particularly on their sensitivity to antibiotics. Thus, G. Taylor and S. Zaloguev observed that bacterial samples collected on the crew during flight in the Apollo-Soyouz Test Project Mission presented higher antibiotic resistance than controls. This paper presents the results of two experiments performed in 1982 and 1985 (Cytos 2 during the French-Soviet Mission and "Antibio" in the Biorack programme of the European Space Agency). The results show an increase of antibiotic resistance in bacteria growth in flight and a modification in the structure of the cell wall. All these modifications are transitory. Two hypotheses are put forward to explain the phenomenon. PMID:3569006

  15. Novel anti-infective molecule from innate immune cells as an antibiotic-alternative to control infections caused by Apicomplexa

    Technology Transfer Automated Retrieval System (TEKTRAN)

    With increasing needs for the global animal industry to address the regulatory restrictions on the use of antibiotic growth promoters (AGPs) in animal production, there is much interest to find alternatives to AGPs. To develop alternatives to antibiotics against the major poultry parasitic disease, ...

  16. Cytometric analysis, genetic manipulation and antibiotic selection of the snail embryonic cell line Bge from Biomphalaria glabrata, the intermediate host of Schistosoma mansoni.

    PubMed

    Rinaldi, Gabriel; Yan, Hongbin; Nacif-Pimenta, Rafael; Matchimakul, Pitchaya; Bridger, Joanna; Mann, Victoria H; Smout, Michael J; Brindley, Paul J; Knight, Matty

    2015-07-01

    The invertebrate cell line, Bge, from embryos of the snail Biomphalaria glabrata, remains to date the only established cell line from any species of the Phylum Mollusca. Since its establishment in 1976 by Eder Hansen, few studies have focused on profiling its cytometrics, growth characteristics or sensitivity to xenobiotics. Bge cells are reputed to be challenging to propagate and maintain. Therefore, even though this cell line is a noteworthy resource, it has not been studied widely. With growing interest in functional genomics, including genetic transformation, to elucidate molecular aspects of the snail intermediate hosts responsible for transmission of schistosomiasis, and aiming to enhance the convenience of maintenance of this molluscan cell line, we deployed the xCELLigene real time approach to study Bge cells. Doubling times for three isolates of Bge, termed CB, SL and UK, were longer than for mammalian cell lines - longer than 40 h in complete Bge medium supplemented with 7% fetal bovine serum at 25°C, ranging from ∼42 h to ∼157 h when 40,000 cells were seeded. To assess the potential of the cells for genetic transformation, antibiotic selection was explored. Bge cells were sensitive to the aminonucleoside antibiotic puromycin (from Streptomyces alboniger) from 5 μg/ml to 200 ng/ml, displaying a half maximal inhibitory concentration (IC50) of ∼1.91 μg/ml. Sensitivity to puromycin, and a relatively quick kill time (<48 h in 5 μg/ml) facilitated use of this antibiotic, together with the cognate resistance gene (puromycin N-acetyl-transferase) for selection of Bge cells transformed with the PAC gene (puroR). Bge cells transfected with a plasmid encoding puroR were partially rescued when cultured in the presence of 5 μg/ml of puromycin. These findings pave the way for the development of functional genomic tools applied to the host-parasite interaction during schistosomiasis and neglected tropical trematodiases at large.

  17. Anti-protozoal and anti-bacterial antibiotics that inhibit protein synthesis kill cancer subtypes enriched for stem cell-like properties

    PubMed Central

    Cuyàs, Elisabet; Martin-Castillo, Begoña; Corominas-Faja, Bruna; Massaguer, Anna; Bosch-Barrera, Joaquim; Menendez, Javier A

    2015-01-01

    Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues. PMID:25970790

  18. Anti-protozoal and anti-bacterial antibiotics that inhibit protein synthesis kill cancer subtypes enriched for stem cell-like properties.

    PubMed

    Cuyàs, Elisabet; Martin-Castillo, Begoña; Corominas-Faja, Bruna; Massaguer, Anna; Bosch-Barrera, Joaquim; Menendez, Javier A

    2015-01-01

    Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues.

  19. Anti-protozoal and anti-bacterial antibiotics that inhibit protein synthesis kill cancer subtypes enriched for stem cell-like properties.

    PubMed

    Cuyàs, Elisabet; Martin-Castillo, Begoña; Corominas-Faja, Bruna; Massaguer, Anna; Bosch-Barrera, Joaquim; Menendez, Javier A

    2015-01-01

    Key players in translational regulation such as ribosomes might represent powerful, but hitherto largely unexplored, targets to eliminate drug-refractory cancer stem cells (CSCs). A recent study by the Lisanti group has documented how puromycin, an old antibiotic derived from Streptomyces alboniger that inhibits ribosomal protein translation, can efficiently suppress CSC states in tumorspheres and monolayer cultures. We have used a closely related approach based on Biolog Phenotype Microarrays (PM), which contain tens of lyophilized antimicrobial drugs, to assess the chemosensitivity profiles of breast cancer cell lines enriched for stem cell-like properties. Antibiotics directly targeting active sites of the ribosome including emetine, puromycin and cycloheximide, inhibitors of ribosome biogenesis such as dactinomycin, ribotoxic stress agents such as daunorubicin, and indirect inhibitors of protein synthesis such as acriflavine, had the largest cytotoxic impact against claudin-low and basal-like breast cancer cells. Thus, biologically aggressive, treatment-resistant breast cancer subtypes enriched for stem cell-like properties exhibit exacerbated chemosensitivities to anti-protozoal and anti-bacterial antibiotics targeting protein synthesis. These results suggest that old/existing microbicides might be repurposed not only as new cancer therapeutics, but also might provide the tools and molecular understanding needed to develop second-generation inhibitors of ribosomal translation to eradicate CSC traits in tumor tissues. PMID:25970790

  20. Antibiotics in dentistry: Bacteremia, antibiotic prophylaxis, and antibiotic misuse.

    PubMed

    Dinsbach, Nathan A

    2012-01-01

    What is known regarding bacteremia? How effective is antibiotic prophylaxis for distant-site infections (late prosthetic joint infections and infective endocarditis)? Antibiotic resistance poses a growing danger to mankind. The misuse of antibiotics is a main cause of antibiotic resistance in bacteria. The author undertook a Medline search and a hand search of the literature regarding bacteremia, antibiotic prophylaxis for late prosthetic joint infections and infective endocarditis, antibiotic misuse, and antibiotic resistance. The findings indicate a clearer understanding of bacteremia emerging in the past 30 years, which has led to recent changes in antibiotic prophylaxis regimens. Dentists should understand how bacteremia affects their at-risk patients, the rationale for antibiotic prophylaxis, and how antibiotic misuse poses a threat to all.

  1. The non-antibiotic macrolide EM900 inhibits rhinovirus infection and cytokine production in human airway epithelial cells

    PubMed Central

    Lusamba Kalonji, Nadine; Nomura, Kazuhiro; Kawase, Tetsuaki; Ota, Chiharu; Kubo, Hiroshi; Sato, Takeya; Yanagisawa, Teruyuki; Sunazuka, Toshiaki; Ōmura, Satoshi; Yamaya, Mutsuo

    2015-01-01

    The anti-inflammatory effects of macrolides may be associated with a reduced frequency of exacerbation of chronic obstructive pulmonary disease (COPD). However, because the long-term use of antibiotics may promote the growth of drug-resistant bacteria, the development of a treatment to prevent COPD exacerbation with macrolides that do not exert anti-bacterial effects is necessary. Additionally, the inhibitory effects of nonantibiotic macrolides on the replication of rhinovirus (RV), which is the major cause of COPD exacerbation, have not been demonstrated. Primary cultures of human tracheal epithelial cells and nasal epithelial cells were pretreated with the nonantibiotic macrolide EM900 for 72 h prior to infection with a major group RV type 14 rhinovirus (RV14) and were further treated with EM900 after infection. Treatment with EM900 before and after infection reduced RV14 titers in the supernatants and viral RNA within the cells. Moreover, cytokine levels, including interleukin (IL)-1β and IL-6, were reduced in the supernatants following RV14 infection. Treatment with EM900 before and after infection also reduced the mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), which is the receptor for RV14, after infection and reduced the activation of the nuclear factor kappa-B protein p50 in nuclear extracts after infection. Pretreatment with EM900 reduced the number and fluorescence intensity of the acidic endosomes through which RV RNA enters the cytoplasm. Thus, pretreatment with EM900 may inhibit RV infection by reducing the ICAM-1 levels and acidic endosomes and thus modulate the airway inflammation associated with RV infections. PMID:26462747

  2. Antibiotics and antibiotic resistance: a bitter fight against evolution.

    PubMed

    Rodríguez-Rojas, Alexandro; Rodríguez-Beltrán, Jerónimo; Couce, Alejandro; Blázquez, Jesús

    2013-08-01

    One of the most terrible consequences of Darwinian evolution is arguably the emergence and spread of antibiotic resistance, which is becoming a serious menace to modern societies. While spontaneous mutation, recombination and horizontal gene transfer are recognized as the main causes of this notorious phenomenon; recent research has raised awareness that sub-lethal concentrations of antibiotics can also foster resistance as an undesirable side-effect. They can produce genetic changes by different ways, including a raise of free radicals within the cell, induction of error-prone DNA-polymerases mediated by SOS response, imbalanced nucleotide metabolism or affect directly DNA. In addition to certain environmental conditions, subinhibitory concentrations of antimicrobials may increase, even more, the mutagenic effect of antibiotics. Here, we review the state of knowledge on antibiotics as promoters of antibiotic resistance.

  3. Ofloxacin-like antibiotics inhibit pneumococcal cell wall-degrading virulence factors.

    PubMed

    Fernández-Tornero, Carlos; García, Ernesto; de Pascual-Teresa, Beatriz; López, Rubens; Giménez-Gallego, Guillermo; Romero, Antonio

    2005-05-20

    The search for new drugs against Streptococcus pneumoniae (pneumococcus) is driven by the 1.5 million deaths it causes annually. Choline-binding proteins attach to the pneumococcal cell wall through domains that recognize choline moieties, and their involvement in pneumococcal virulence makes them potential targets for drug development. We have defined chemical criteria involved in the docking of small molecules from a three-dimensional structural library to the major pneumococcal autolysin (LytA) choline binding domain. These criteria were used to identify compounds that could interfere with the attachment of this protein to the cell wall, and several quinolones that fit this framework were found to inhibit the cell wall-degrading activity of LytA. Furthermore, these compounds produced similar effects on other enzymes with different catalytic activities but that contained a similar choline binding domain; that is, autolysin (LytC) and the phage lytic enzyme (Cpl-1). Finally, we resolved the crystal structure of the complex between the choline binding domain of LytA and ofloxacin at a resolution of 2.6 Angstroms. These data constitute an important launch pad from which effective drugs to combat pneumococcal infections can be developed.

  4. Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination

    PubMed Central

    Wang, Xiaorong; Kang, Yu; Luo, Chunxiong; Zhao, Tong; Liu, Lin; Jiang, Xiangdan; Fu, Rongrong; An, Shuchang; Chen, Jichao; Jiang, Ning; Ren, Lufeng; Wang, Qi; Baillie, J. Kenneth; Gao, Zhancheng; Yu, Jun

    2014-01-01

    ABSTRACT Heteroresistance refers to phenotypic heterogeneity of microbial clonal populations under antibiotic stress, and it has been thought to be an allocation of a subset of “resistant” cells for surviving in higher concentrations of antibiotic. The assumption fits the so-called bet-hedging strategy, where a bacterial population “hedges” its “bet” on different phenotypes to be selected by unpredicted environment stresses. To test this hypothesis, we constructed a heteroresistance model by introducing a blaCTX-M-14 gene (coding for a cephalosporin hydrolase) into a sensitive Escherichia coli strain. We confirmed heteroresistance in this clone and that a subset of the cells expressed more hydrolase and formed more colonies in the presence of ceftriaxone (exhibited stronger “resistance”). However, subsequent single-cell-level investigation by using a microfluidic device showed that a subset of cells with a distinguishable phenotype of slowed growth and intensified hydrolase expression emerged, and they were not positively selected but increased their proportion in the population with ascending antibiotic concentrations. Therefore, heteroresistance—the gradually decreased colony-forming capability in the presence of antibiotic—was a result of a decreased growth rate rather than of selection for resistant cells. Using a mock strain without the resistance gene, we further demonstrated the existence of two nested growth-centric feedback loops that control the expression of the hydrolase and maximize population growth in various antibiotic concentrations. In conclusion, phenotypic heterogeneity is a population-based strategy beneficial for bacterial survival and propagation through task allocation and interphenotypic collaboration, and the growth rate provides a critical control for the expression of stress-related genes and an essential mechanism in responding to environmental stresses. PMID:24520060

  5. Efficient mineralization of the antibiotic trimethoprim by solar assisted photoelectro-Fenton process driven by a photovoltaic cell.

    PubMed

    Zhang, Yanyu; Wang, Aimin; Tian, Xiujun; Wen, Zhenjun; Lv, Hanjiao; Li, Desheng; Li, Jiuyi

    2016-11-15

    In this study, a novel self-sustainable solar assisted photoelectro-Fenton (SPEF) system driven by a solar photovoltaic cell was developed for the efficient mineralization of antibiotic trimethoprim (TMP) in water. A comparative degradation of 200mgL(-1) TMP by RuO2/Ti anodic oxidation (AO), anodic oxidation with H2O2 electrogeneration (AO-H2O2), electro-Fenton (EF) and SPEF was investigated. SPEF was proved to exhibit the highest oxidation power, i.e., more than 80% TOC was removed after 360min SPEF treatment of 200mgL(-1) of TMP under optimal conditions at pH 3.0, 1.0mM Fe(2+) and 18mAcm(-2). Influences of current density, pH, initial Fe(2+) and initial TMP concentration on SPEF process were also studied. Ten aromatic intermediates generated from hydroxylation, carbonylation and demethylation reactions were identified using UPLC-QTOF-MS/MS system during the SPEF treatment, together with three carboxylic acids (oxamic, oxalic and formic acids) and two inorganic ions (NH4(+) and NO3(-)) measured. Therefore, a reasonable pathway of TMP degradation in SPEF process was proposed.

  6. Efficient mineralization of the antibiotic trimethoprim by solar assisted photoelectro-Fenton process driven by a photovoltaic cell.

    PubMed

    Zhang, Yanyu; Wang, Aimin; Tian, Xiujun; Wen, Zhenjun; Lv, Hanjiao; Li, Desheng; Li, Jiuyi

    2016-11-15

    In this study, a novel self-sustainable solar assisted photoelectro-Fenton (SPEF) system driven by a solar photovoltaic cell was developed for the efficient mineralization of antibiotic trimethoprim (TMP) in water. A comparative degradation of 200mgL(-1) TMP by RuO2/Ti anodic oxidation (AO), anodic oxidation with H2O2 electrogeneration (AO-H2O2), electro-Fenton (EF) and SPEF was investigated. SPEF was proved to exhibit the highest oxidation power, i.e., more than 80% TOC was removed after 360min SPEF treatment of 200mgL(-1) of TMP under optimal conditions at pH 3.0, 1.0mM Fe(2+) and 18mAcm(-2). Influences of current density, pH, initial Fe(2+) and initial TMP concentration on SPEF process were also studied. Ten aromatic intermediates generated from hydroxylation, carbonylation and demethylation reactions were identified using UPLC-QTOF-MS/MS system during the SPEF treatment, together with three carboxylic acids (oxamic, oxalic and formic acids) and two inorganic ions (NH4(+) and NO3(-)) measured. Therefore, a reasonable pathway of TMP degradation in SPEF process was proposed. PMID:27434735

  7. Factors influencing variation of bulk milk antibiotic residue occurrence, somatic cell count, and total bacterial count in dairy sheep flocks.

    PubMed

    Gonzalo, C; Carriedo, J A; García-Jimeno, M C; Pérez-Bilbao, M; de la Fuente, L F

    2010-04-01

    To study the variations of bulk tank milk variables in dairy ewe flocks and to identify the main target practices and flock groups to improve milk quality and safety, a total of 71,228 records of antibiotic residue (AR) and milk yield and 68,781 records of somatic cell count (SCC) and total bacterial count (TBC) were obtained over 5 yr from the same 209 dairy ewe flocks of the Assaf breed belonging to the Consortium for Ovine Promotion of Castilla-León (Spain). Based on a logistic regression model, year, month, semester, SCC, TBC, dry therapy, and milk yield significantly contributed to AR variation. High SCC was associated with increased AR violations. When antibiotic dry therapy was implemented, AR occurrence was higher than when this practice was not used. A polynomial monthly distribution throughout the year was observed for AR occurrence; the highest values were in autumn, coinciding with low milk yields per flock. Yearly occurrences drastically diminished from 2004 (1.36%) to 2008 (0.30%), probably as a result of effective educational programs. The mixed-model ANOVA of factors influencing variation in SCC and TBC indicated that year, month, AR, dry therapy group, milking type, and year interactions were significant variation factors for SCC and TBC; mathematical model accounted for 74.1 and 35.4% of total variance for each variable, respectively. Differences in management and hygiene practice caused significant SCC and TBC variations among flocks and within flocks throughout the 5-yr study. Over time, continuously dry treated flocks showed lower logSCC (5.80) and logTBC (4.92) than untreated (6.10 and 5.18, respectively) or discontinuously dry treated (6.01 and 5.05, respectively) flocks. Continuously dry treated flocks had lower AR occurrences than did discontinuously dry treated flocks. As a whole, AR occurrence and SCC and TBC bulk tank milk variables can be used for monitoring mammary health and milk hygiene and safety in dairy sheep throughout time.

  8. Cytotoxicity of macrolide antibiotics in a cultured human liver cell line.

    PubMed

    Viluksela, M; Vainio, P J; Tuominen, R K

    1996-09-01

    Cytotoxicity of erythromycin base, erythromycin estolate, erythromycin-11,12-cyclic carbonate, roxithromycin, clarithromycin and azithromycin was compared in cultured human non-malignant Chang liver cells using reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and cellular protein concentration as end points of toxicity. Erythromycin estolate was the most toxic macrolide in all tests differing clearly from all the other macrolides studied. Erythromycin-11,12-cyclic carbonate was also more toxic than the other macrolides. Roxithromycin and clarithromycin were the next toxic derivatives, while erythromycin base and azithromycin were least toxic. Thus, cytotoxicity of the new semisynthetic macrolides, roxithromycin, clarithromycin and azithromycin, is not substantially different from that of erythromycin base. In view of the low level of hepatotoxicity of macrolides hitherto reported in humans, the results do not suggest any substantial risk for hepatic disorders related to the use of azithromycin, clarithromycin and roxithromycin.

  9. Delivery of antibiotics with polymeric particles.

    PubMed

    Xiong, Meng-Hua; Bao, Yan; Yang, Xian-Zhu; Zhu, Yan-Hua; Wang, Jun

    2014-11-30

    Despite the wide use of antibiotics, bacterial infection is still one of the leading causes of hospitalization and mortality. The clinical failure of antibiotic therapy is linked with low bioavailability, poor penetration to bacterial infection sites, and the side effects of antibiotics, as well as the antibiotic resistance properties of bacteria. Antibiotics encapsulated in nanoparticles or microparticles made up of a biodegradable polymer have shown great potential in replacing the administration of antibiotics in their "free" form. Polymeric particles provide protection to antibiotics against environmental deactivation and alter antibiotic pharmacokinetics and biodistribution. Polymeric particles can overcome tissue and cellular barriers and deliver antibiotics into very dense tissues and inaccessible target cells. Polymeric particles can be modified to target or respond to particular tissues, cells, and even bacteria, and thereby facilitate the selective concentration or release of the antibiotic at infection sites, respectively. Thus, the delivery of antibiotics with polymeric particles augments the level of the bioactive drug at the site of infection while reducing the dosage and the dosing frequency. The end results are improved therapeutic effects as well as decreased "pill burden" and drug side effects in patients. The main objective of this review is to analyze recent advances and current perspectives in the use of polymeric antibiotic delivery systems in the treatment of bacterial infection.

  10. [Action of antibiotics as signalling molecules].

    PubMed

    Bulgakova, V G; Vinogradova, K A; Orlova, T I; Kozhevin, P A; Polin, A N

    2014-01-01

    It was thought that antibiotics should be produced by soil microorganisms to inhibit the growth of competitors in natural habitats. Yet it has been shown that antibiotics at subinhibitory concentrations may have a role as signalling molecules providing cell-to-cell communication in bacteria in the environment. Antibiotics modulate gene transcription and regulate gene expression in microbial populations. Subinhibitory concentrations of antibiotics may cause a number of phenotypic and genotypic changes in microorganisms. These transcription changes are dependent on the interaction of antibiotics with macromolecular receptors such as ribosome or RNA-polymerase. Antibiotic signalling and quorum-sensing system are important regulatory mechanisms in bacteria. It was demonstrated that antibiotics interfered with quorum-sensing system.

  11. Inhibition of RNA synthesis in vitro and cell growth by anthracycline antibiotics.

    PubMed

    Studzian, K; Wasowska, M; Piestrzeniewicz, M K; Wilmańska, D; Szmigiero, L; Oszczapowicz, I; Gniazdowski, M

    2001-01-01

    New derivatives of doxorubicin and daunorubicin with amidine group bonded to daunosamine at C-3' atom and bearing the morpholine ring attached to the amidine group have been recently synthesized. Their cytotoxic activities and effects on RNA synthesis in vitro were assayed. The drug concentrations inhibiting mouse leukaemia L1210 cell growth to 50% were about two- and three fold higher for the derivatives compared to doxorubicin and daunorubicin respectively. Inhibition of phage T7 RNA polymerase by the non-covalently interacting derivatives was also slightly lower than that by the parent compounds. As doxorubicin and daunorubicin, their amidine derivatives in the presence of dithiothreitol and Fe(III) ions are activated and covalently bind to DNA. The adducts formed affect RNA polymerase activity. Several bands corresponding to prematurely terminated RNA chains are observed by means of polyacrylamide gel electrophoresis. The patterns of bands are virtually identical for all the anthracyclines studied here and are similar to the terminations induced by actinomycin D. This observation is consistent with a notion that the adducts are formed at guanine in GpC sequences which are also binding sites of actinomycin D. A substantial difference between daunorubicin and its amidine derivative is shown by means of high performance liquid chromatography. The derivative undergoes rapid rearrangements in the presence of dithiothreitol and Fe(III) ions, while daunorubicin is stable for several hours under these conditions. The results presented here indicate that the amidine derivatives despite bulky morpholine substitution exhibit biological activity in the systems used here. PMID:11845988

  12. The Role of Reactive Oxygen Species in Antibiotic-Induced Cell Death in Burkholderia cepacia Complex Bacteria

    PubMed Central

    Van Acker, Heleen; Gielis, Jan; Acke, Marloes; Cools, Freya; Cos, Paul

    2016-01-01

    It was recently proposed that bactericidal antibiotics, besides through specific drug-target interactions, kill bacteria by a common mechanism involving the production of reactive oxygen species (ROS). However, this mechanism involving the production of hydroxyl radicals has become the subject of a lot of debate. Since the contribution of ROS to antibiotic mediated killing most likely depends on the conditions, differences in experimental procedures are expected to be at the basis of the conflicting results. In the present study different methods (ROS specific stainings, gene-expression analyses, electron paramagnetic resonance, genetic and phenotypic experiments, detection of protein carbonylation and DNA oxidation) to measure the production of ROS upon antibiotic treatment in Burkholderia cepacia complex (Bcc) bacteria were compared. Different classes of antibiotics (tobramycin, ciprofloxacin, meropenem) were included, and both planktonic and biofilm cultures were studied. Our results indicate that some of the methods investigated were not sensitive enough to measure antibiotic induced production of ROS, including the spectrophotometric detection of protein carbonylation. Secondly, other methods were found to be useful only in specific conditions. For example, an increase in the expression of OxyR was measured in Burkholderia cenocepacia K56-2 after treatment with ciprofloxacin or meropenem (both in biofilms and planktonic cultures) but not after treatment with tobramycin. In addition results vary with the experimental conditions and the species tested. Nevertheless our data strongly suggest that ROS contribute to antibiotic mediated killing in Bcc species and that enhancing ROS production or interfering with the protection against ROS may form a novel strategy to improve antibiotic treatment. PMID:27438061

  13. Annexin A2 is a target of autoimmune T and B cell responses associated with synovial fibroblast proliferation in patients with antibiotic-refractory Lyme arthritis.

    PubMed

    Pianta, Annalisa; Drouin, Elise E; Crowley, Jameson T; Arvikar, Sheila; Strle, Klemen; Costello, Catherine E; Steere, Allen C

    2015-10-01

    In this study, autoantibody responses to annexin A2 were found in 11-15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings.

  14. Annexin A2 Is a Target of Autoimmune T and B Cell Responses Associated with Synovial Fibroblast Proliferation in Patients with Antibiotic-Refractory Lyme Arthritis

    PubMed Central

    Pianta, Annalisa; Drouin, Elise E.; Crowley, Jameson T.; Arvikar, Sheila; Strle, Klemen; Costello, Catherine E.; Steere, Allen C.

    2015-01-01

    In this study, autoantibody responses to annexin A2 were found in 11–15% of 278 patients with Lyme disease, including in those with erythema migrans (EM), an early sign of the illness, and in those with antibiotic-responsive or antibiotic-refractory Lyme arthritis (LA), a late disease manifestation. In contrast, robust T cell reactivity to annexin A2 peptides was found only in patients with responsive or refractory LA. In LA patients, annexin A2 protein levels, which were higher in the refractory group, correlated with annexin A2 antibody levels in sera and synovial fluid. In addition, in patients with antibiotic-refractory LA who had anti-annexin A2 antibodies, synovial tissue had intense staining for annexin A2 protein, greater synovial fibroblast proliferation and more tissue fibrosis. Thus, a subset of LA patients had T and B cell responses to annexin A2, and in the refractory group, annexin A2 autoantibodies were associated with specific pathologic findings. PMID:26187145

  15. Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells

    PubMed Central

    2011-01-01

    Background Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics. PMID:21418624

  16. Facts about Antibiotic Resistance

    MedlinePlus

    ... Trends and Cost Español: Datos breves Facts about Antibiotic Resistance Antibiotic resistance has been called one of the world’s most ... antibiotic use is a key strategy to control antibiotic resistance. Antibiotic resistance in children is of particular concern ...

  17. Modular synthesis of diphospholipid oligosaccharide fragments of the bacterial cell wall and their use to study the mechanism of moenomycin and other antibiotics.

    PubMed

    Gampe, Christian M; Tsukamoto, Hirokazu; Wang, Tsung-Shing Andrew; Walker, Suzanne; Kahne, Daniel

    2011-12-23

    We present a flexible, modular route to GlcNAc-MurNAc-oligosaccharides that can be readily converted into peptidoglycan (PG) fragments to serve as reagents for the study of bacterial enzymes that are targets for antibiotics. Demonstrating the utility of these synthetic PG substrates, we show that the tetrasaccharide substrate lipid IV (3), but not the disaccharide substrate lipid II (2), significantly increases the concentration of moenomycin A required to inhibit a prototypical PG-glycosyltransferase (PGT). These results imply that lipid IV and moenomycin A bind to the same site on the enzyme. We also show the moenomycin A inhibits the formation of elongated polysaccharide product but does not affect length distribution. We conclude that moenomycin A blocks PG-strand initiation rather than elongation or chain termination. Synthetic access to diphospholipid oligosaccharides will enable further studies of bacterial cell wall synthesis with the long-term goal of identifying novel antibiotics.

  18. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

    PubMed Central

    Shono, Yusuke; Docampo, Melissa D.; Peled, Jonathan U.; Perobelli, Suelen M.; Velardi, Enrico; Tsai, Jennifer J.; Slingerland, Ann E.; Smith, Odette M.; Young, Lauren F.; Gupta, Jyotsna; Lieberman, Sophia R.; Jay, Hillary V.; Ahr, Katya F.; Rodriguez, Kori A. Porosnicu; Xu, Ke; Calarfiore, Marco; Poeck, Hendrik; Caballero, Silvia; Devlin, Sean M.; Rapaport, Franck; Dudakov, Jarrod A.; Hanash, Alan M.; Gyurkocza, Boglarka; Murphy, George F.; Gomes, Camilla; Liu, Chen; Moss, Eli L.; Falconer, Shannon B.; Bhatt, Ami S.; Taur, Ying; Pamer, Eric G.

    2016-01-01

    After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after

  19. Outer Membrane Permeability and Antibiotic Resistance

    PubMed Central

    Delcour, Anne H.

    2009-01-01

    Summary To date most antibiotics are targeted at intracellular processes, and must be able to penetrate the bacterial cell envelope. In particular, the outer membrane of Gram-negative bacteria provides a formidable barrier that must be overcome. There are essentially two pathways that antibiotics can take through the outer membrane: a lipid-mediated pathway for hydrophobic antibiotics, and general diffusion porins for hydrophilic antibiotics. The lipid and protein compositions of the outer membrane have a strong impact on the sensitivity of bacteria to many types of antibiotics, and drug resistance involving modifications of these macromolecules is common. This review will describe the molecular mechanisms for permeation of antibiotics through the outer membrane, and the strategies that bacteria have deployed to resist antibiotics by modifications of these pathways. PMID:19100346

  20. Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte‐derived dendritic cells

    SciTech Connect

    Sebastian, Katrin; Ott, Hagen; Zwadlo-Klarwasser, Gabriele; Skazik-Voogt, Claudia; Marquardt, Yvonne; Czaja, Katharina; Merk, Hans F.; Baron, Jens Malte

    2012-08-01

    Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides – which are the most frequent cause of adverse drug reactions – were co-incubated with THP-1, MUTZ-LC, or primary monocyte‐derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1β, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines. -- Highlights: ► We tested the sensitizing potential of small molecular weight drugs in vitro. ► In vitro assays were performed with moDCs and THP-1 cells. ► Beta-lactam antibiotics can be recognized as sensitizing compounds. ► They affect the expression of metabolic enzymes, cytokines and transcription factors. ► Sulfamethoxazole has no measurable effect on THP-1 cells and moDCs.

  1. The membrane protein PrsS mimics σS in protecting Staphylococcus aureus against cell wall-targeting antibiotics and DNA-damaging agents

    PubMed Central

    Krute, Christina N.; Bell-Temin, Harris; Miller, Halie K.; Rivera, Frances E.; Weiss, Andy; Stevens, Stanley M.

    2015-01-01

    Staphylococcus aureus possesses a lone extracytoplasmic function (ECF) sigma factor, σS. In Bacillus subtilis, the ECF sigma factor, σW, is activated through a proteolytic cascade that begins with cleavage of the RsiW anti-sigma factor by a site-1 protease (S1P), PrsW. We have identified a PrsW homologue in S. aureus (termed PrsS) and explored its role in σS regulation. Herein, we demonstrate that although a cognate σS anti-sigma factor currently remains elusive, prsS phenocopies sigS in a wealth of regards. Specifically, prsS expression mimics the upregulation observed for sigS in response to DNA-damaging agents, cell wall-targeting antibiotics and during ex vivo growth in human serum and murine macrophages. prsS mutants also display the same sensitivities of sigS mutants to the DNA-damaging agents methyl methane sulfonate (MMS) and hydrogen peroxide, and the cell wall-targeting antibiotics ampicillin, bacitracin and penicillin-G. These phenotypes appear to be explained by alterations in abundance of proteins involved in drug resistance (Pbp2a, FemB, HmrA) and the response to DNA damage (BmrA, Hpt, Tag). Our findings seem to be mediated by putative proteolytic activity of PrsS, as site-directed mutagenesis of predicted catalytic residues fails to rescue the sensitivity of the mutant to H2O2 and MMS. Finally, a role for PrsS in S. aureus virulence was identified using human and murine models of infection. Collectively, our data indicate that PrsS and σS function in a similar manner, and perhaps mediate virulence and resistance to DNA damage and cell wall-targeting antibiotics, via a common pathway. PMID:25741016

  2. Development of Multiple Antibiotic Resistance in Bacillus subtilis Cells Exposed to Microgravity: the BRIC-18 Experiment to the International Space Station

    NASA Astrophysics Data System (ADS)

    Fajardo-Cavazos, Patricia; Moeller, Ralf; Nicholson, Wayne; Narvel, Raed

    Increased pathogenicity of opportunistic bacteria during long-term spaceflight is considered an astronaut risk. Because only a limited pharmacy can be carried on long-duration missions, the development of resistance to multiple antibiotics is a concern for mission planning. In support of the BRIC-18 experiment to the ISS, we have performed ground-based experiments to address the question whether simulated microgravity affects the frequency of resistance to the model antibiotics rifampicin (RFM) and trimethoprim (TMP). In these experiments, the model bacteria Bacillus subtilis and Staphylococcus epidermidis were cultivated for 6 days at ISS ambient temperature in 10-ml High Aspect Ratio Vessels (HARVs) on two 4-place clinostats (Synthecon) oriented either vertically (V) or horizontally (H). Cells were harvested, enumerated and plated onto medium containing RFM (5 micrograms/ml). The frequency of mutation to RFM resistance was calculated, and RFM-resistant mutants were plated onto medium containing the second antibiotic, TMP (5 micrograms/ml) to determine the frequency of mutation to double (RFM+TMP) resistance. After 6 days of cultivation, V-cultures showed higher cell densities and than H-cultures for both bacteria. However, only in B. subtilis did V-cultures show higher frequencies of mutation to RFM resistance than H-cultures. Launch of BRIC-18 to the ISS is currently scheduled for March 16, 2014 and return 30 days later. Results from both the spaceflight and ground control experiments will be presented. Supported by NASA-SAIP fellowship to R.N. and NASA grant (NNX12AN70G) to P.F.-C., R.M., and W.L.N.

  3. [Rapid antibiotic susceptibility test in Clinical Microbiology].

    PubMed

    March Rosselló, Gabriel Alberto; Bratos Pérez, Miguel Ángel

    2016-01-01

    The most widely used antibiotic susceptibility testing methods in Clinical Microbiology are based on the phenotypic detection of antibiotic resistance by measuring bacterial growth in the presence of the antibiotic being tested. These conventional methods take typically 24hours to obtain results. A review is presented here of recently developed techniques for the rapid determination of antibiotic susceptibility. Data obtained with different methods such as molecular techniques, flow cytometry, chemiluminescence, mass spectrometry, commercial methods used in routine work, colorimetric methods, nephelometry, microarrays, microfluids, and methods based on cell disruption and sequencing, are analyzed and discussed in detail.

  4. Bacteria subsisting on antibiotics.

    PubMed

    Dantas, Gautam; Sommer, Morten O A; Oluwasegun, Rantimi D; Church, George M

    2008-04-01

    Antibiotics are a crucial line of defense against bacterial infections. Nevertheless, several antibiotics are natural products of microorganisms that have as yet poorly appreciated ecological roles in the wider environment. We isolated hundreds of soil bacteria with the capacity to grow on antibiotics as a sole carbon source. Of 18 antibiotics tested, representing eight major classes of natural and synthetic origin, 13 to 17 supported the growth of clonal bacteria from each of 11 diverse soils. Bacteria subsisting on antibiotics are surprisingly phylogenetically diverse, and many are closely related to human pathogens. Furthermore, each antibiotic-consuming isolate was resistant to multiple antibiotics at clinically relevant concentrations. This phenomenon suggests that this unappreciated reservoir of antibiotic-resistance determinants can contribute to the increasing levels of multiple antibiotic resistance in pathogenic bacteria. PMID:18388292

  5. Gardimycin, a New Antibiotic Inhibiting Peptidoglycan Synthesis

    PubMed Central

    Somma, Sergio; Merati, Wilma; Parenti, Francesco

    1977-01-01

    Gardimycin, a new antibiotic, at 100 μg/ml, specifically inhibited cell wall synthesis and induced accumulation of uridine 5′-diphosphate-N-acetylmur-amylpentapeptide in whole cells of Bacillus subtilis. The antibiotic was active in a particulate enzyme preparation from Bacillus stearothermophilus: 60 μg/ml caused 50%, and 200μg/ml caused 100%, inhibition of peptidoglycan synthesis. Suppression of peptidoglycan synthesis was accompanied by parallel accumulation of the lipid intermediate. This mechanism of action is discussed in comparison with those of other antibiotics that are known to inhibit bacterial cell wall biosynthesis. PMID:404960

  6. Concentration-dependent activity of antibiotics in natural environments

    PubMed Central

    Bernier, Steve P.; Surette, Michael G.

    2013-01-01

    Bacterial responses to antibiotics are concentration-dependent. At high concentrations, antibiotics exhibit antimicrobial activities on susceptible cells, while subinhibitory concentrations induce diverse biological responses in bacteria. At non-lethal concentrations, bacteria may sense antibiotics as extracellular chemicals to trigger different cellular responses, which may include an altered antibiotic resistance/tolerance profile. In natural settings, microbes are typically in polymicrobial communities and antibiotic-mediated interactions between species may play a significant role in bacterial community structure and function. However, these aspects have not yet fully been explored at the community level. Here we discuss the different types of interactions mediated by antibiotics and non-antibiotic metabolites as a function of their concentrations and speculate on how these may amplify the overall antibiotic resistance/tolerance and the spread of antibiotic resistance determinants in a context of polymicrobial community. PMID:23422936

  7. Antibiotics and Resistance: Glossary

    MedlinePlus

    ... induced by natural or human activity on the ecology and living organisms. Ecology The study of the relationships and interactions between ... antibiotics The Cost of Resistance Science of Resistance Ecology Antibiotics in Agriculture Antibacterial Agents Glossary References Web ...

  8. Combating Antibiotic Resistance

    MedlinePlus

    ... for infectious diseases. back to top Antibiotics Fight Bacteria, Not Viruses Antibiotics are meant to be used ... treat strep throat, which is caused by streptococcal bacteria, and skin infections caused by staphylococcal bacteria. Although ...

  9. Cooperative Antibiotic Resistance in a Multi-Drug Environment

    NASA Astrophysics Data System (ADS)

    Yurtsev, Eugene; Dai, Lei; Gore, Jeff

    2013-03-01

    The emergence of antibiotic resistance in bacteria is a significant health concern. A frequent mechanism of antibiotic resistance involves the production of an enzyme which inactivates the antibiotic. By inactivating the antibiotic, resistant cells can ``share'' their resistance with other cells in the bacterial population, suggesting that it may be possible to observe cooperation between strains that inactivate different antibiotics. Here, we experimentally track the population dynamics of two E. coli strains in the presence of two different antibiotics. We find that together the strains are able to grow in antibiotic concentrations that inhibit growth of either of the strains individually. We observe that even when there is stable coexistence between the two strains, the population size of each strain can undergo large oscillations. We expect that our results will provide insight into the evolution of antibiotic resistance and the evolutionary origin of phenotypic diversity and cooperative behaviors.

  10. [Effect of triterpene glycosides and polyene antibiotics on cell membrane permeability for K+ ions and UV-absorbing substances].

    PubMed

    Anisimov, M M; Ivanova, A S; Popov, A M; Kiseleva, M I; Sebko, I G

    1981-01-01

    The effect of triterpene glycosides (cauloside C from Caulophyllum robustum, theasaponine from Thea sinensis, cucumarioside G from Cucumaria fraudatrix stichoposide A from Stichopus japonicus S., holothurines A and B from Holothuria mexicana, holothurine C from Bohadschia sp.) on the membrane permeability for K+ ions and UV-absorbing substances was compared with that of polyene antibiotics, viz., amphotericine B and nystatine. As a biological model fertilized eggs of sea urchin Strongylocentrotus nudus and yeast Saccharomyces carlsbergensis were used. In the sea urchin study most triterpene glycosides in low concentrations induced the outflux of K+ and in hgih concentrations that of both K+ and UV-absorbing agents. In the yeast study triterpene glycosides at identical doses induced the outflux of both K+ and UV-absorbing agents. The membranotropic effect of triterpene glycosides depended on the medium temperature and the biological system used.

  11. Reversibility of antibiotic resistance

    PubMed Central

    2014-01-01

    Although theoretically attractive, the reversibility of resistance has proven difficult in practice, even though antibiotic resistance mechanisms induce a fitness cost to the bacterium. Associated resistance to other antibiotics and compensatory mutations seem to ameliorate the effect of antibiotic interventions in the community. In this paper the current understanding of the concepts of reversibility of antibiotic resistance and the interventions performed in hospitals and in the community are reviewed. PMID:24836051

  12. On the local applications of antibiotics and antibiotic-based agents in endodontics and dental traumatology.

    PubMed

    Mohammadi, Z; Abbott, P V

    2009-07-01

    Antibiotics are a valuable adjunctive to the armamentarium available to health professionals for the management of bacterial infections. During endodontic treatment and when managing trauma to the teeth, antibiotics may be applied systemically (orally and/or parenterally) or locally (i.e. intra-dentally via irrigants and medicaments). Due to the potential risk of adverse effects following systemic application, and the ineffectiveness of systemic antibiotics in necrotic pulpless teeth and the periradicular tissues, the local application of antibiotics may be a more effective mode for delivery in endodontics. The aim of this article was to review the history, rationale and applications of antibiotic-containing irrigants and medicaments in endodontics and dental traumatology. The search was performed from 1981 to 2008 and was limited to English-language papers. The keywords searched on Medline were 'Antibiotics AND endodontics', 'Antibiotics AND root canal irrigation', 'Antibiotics AND intra-canal medicament', 'Antibiotics AND Dental trauma' and 'Antibiotics AND root resorption'. The reference section of each article was manually searched to find other suitable sources of information. It seems that local routes of antibiotic administration are a more effective mode than systemic applications. Various antibiotics have been tested in numerous studies and each has some advantages. Tetracyclines are a group of bacteriostatic antibiotics with antibacterial substantivity for up to 12 weeks. They are typically used in conjunction with corticosteroids and these combinations have anti-inflammatory, anti-bacterial and anti-resorptive properties, all of which help to reduce the periapical inflammatory reaction including clastic-cell mediated resorption. Tetracyclines have also been used as part of irrigating solutions but the substantivity is only for 4 weeks. Clindamycin and a combination of three antibiotics (metronidazole, ciprofloxacin and minocycline) have also been

  13. Finding alternatives to antibiotics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The spread of antibiotic-resistant pathogens requires new treatments. The availability of new antibiotics has severely declined, and so alternatives to antibiotics need to be considered in both animal agriculture and human medicine. Products for disease prevention are different than products for d...

  14. Antibiotic resistant in microorganisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antimicrobial agents are necessary for use in veterinary medicine including the production of food producing animals. Antibiotic use is indicated for the treatment of bacterial target organisms and/or disease for which the antibiotic was developed. However, an unintended consequence of antibiotic ...

  15. Antibiotic Resistance Questions and Answers

    MedlinePlus

    ... on the Farm Get Smart About Antibiotics Week Antibiotic Resistance Questions and Answers Language: English Español (Spanish) Recommend ... Many ear infections Top of Page Questions about Antibiotic Resistance Examples of How Antibiotic Resistance Spreads Click for ...

  16. Pseudomonas aeruginosa cells adapted to benzalkonium chloride show resistance to other membrane-active agents but not to clinically relevant antibiotics.

    PubMed

    Loughlin, M F; Jones, M V; Lambert, P A

    2002-04-01

    Our objective was to determine whether strains of Pseudomonas aeruginosa can adapt to growth in increasing concentrations of the disinfectant benzalkonium chloride (BKC), and whether co-resistance to clinically relevant antimicrobial agents occurs. Attempts were made to determine what phenotypic alterations accompanied resistance and whether these explained the mechanism of resistance. Strains were serially passaged in increasing concentrations of BKC in static nutrient broth cultures. Serotyping and genotyping were used to determine purity of the cultures. Two strains were examined for cross-resistance to other disinfectants and antibiotics by broth dilution MIC determination. Alterations in outer membrane proteins and lipopolysaccharide (LPS) expressed were examined by SDS-PAGE. Cell surface hydrophobicity and charge, uptake of disinfectant and proportion of specific fatty acid content of outer and cytoplasmic membranes were determined. Two P. aeruginosa strains showed a stable increase in resistance to BKC. Co-resistance to other quaternary ammonium compounds was observed in both strains; chloramphenicol and polymyxin B resistance were observed in one and a reduction in resistance to tobramycin observed in the other. However, no increased resistance to other biocides (chlorhexidine, triclosan, thymol) or antibiotics (ceftazidime, imipenem, ciprofloxacin, tobramycin) was detected. Characteristics accompanying resistance included alterations in outer membrane proteins, uptake of BKC, cell surface charge and hydrophobicity, and fatty acid content of the cytoplasmic membrane, although no evidence was found for alterations in LPS. Each of the two strains had different alterations in phenotype, indicating that such adaptation is unique to each strain of P. aeruginosa and does not result from a single mechanism shared by the whole species. PMID:11909837

  17. The peculiar N- and (-termini of trichogin GA IV are needed for membrane interaction and human cell death induction at doses lacking antibiotic activity.

    PubMed

    Tavano, Regina; Malachin, Giulia; De Zotti, Marta; Peggion, Cristina; Biondi, Barbara; Forrnaggio, Fernando; Papini, Emanuele

    2015-01-01

    Peptaibiotics, non-ribosomally synthetized peptides from various ascomycetes, are uniquely characterized by dialkylated a-amino acids, a rigid heli cal conformation, and membrane permeation properties. Although generally considered as antimicrobial peptides, peptaibiotics may display other toxicological properties, and their function is in many cases unknown. With the goal to define the biological activity and selectivity of the peptaibiotictrichogin GA IV from the human opportunist Trichodenna longibrachiatum we analyzed its membrane interaction,cytotoxic activity and antibacterial effect. Trichogin GA IV effectively killed several types of healthy and neoplastic human cells at doses (EC 50%= 4-6 ~) lacking antibiotic effects on both Gram- and Gram+ bacteria(MIC > 64 ~ ). The peptaibiotic distinctive (-terminal primary alcohol was found to cooperate with theN-terminal n-octanoyl group to permeate the membrane phospholipid bilayer and to mediate effective binding and active endocytosis of trichogin GA IV in eukaryotic cells, two steps essential for cell death induction.Replacement of one Gly with Lys plus the simultaneous esterification of the (-terminus, strongly increased trichogin GA IV anti-Gram+ activity (MIC 1-4 ~ ). but further mitigated its cytotoxicity on human cells. PMID:25306964

  18. Dorrigocins: novel antifungal antibiotics that change the morphology of ras-transformed NIH/3T3 cells to that of normal cells. II. Isolation and elucidation of structures.

    PubMed

    Hochlowski, J E; Whittern, D N; Hill, P; McAlpine, J B

    1994-08-01

    Two novel antifungal antibiotics, named dorrigocin A and B have been isolated from the fermentation broth and mycelium of Streptomyces platensis subsp. rosaceus. These closely related compounds were separated from one another by countercurrent chromatography on an Ito coil planet centrifuge. The structures of the dorrigocins were determined by NMR and IR spectroscopy and mass spectrometry. Each is a putative propionate-acetate derived straight chain fatty acid terminating in cycloheximide. The dorrigocins differ from one another only in their oxidation pattern.

  19. Mutant of Escherichia coli with Anomalous Cell Division and Ability to Decrease Episomally and Chromosomally Mediated Resistance to Ampicillin and Several Other Antibiotics

    PubMed Central

    Normark, Staffan; Boman, Hans G.; Matsson, Eva

    1969-01-01

    In a mutation experiment with a rough, ampicillin-resistant strain, we isolated two smooth mutants which were both sensitive to ampicillin and carried defects in the cell envelope. One of the strains (with the envA gene) is hindered in its completion of septa and forms chains of cells. The envA gene has been mapped to a position between leu and proB, at 2 to 4 min. The envA gene decreased the resistance mediated by both episomal and chromosomal genes for resistance to several antibiotics. During growth the envA mutant was characterized by abnormal ratios between viable count or cell count and optical density. The ratio between viable count and optical density was affected during shift-up and shift-down experiments. When compared to the parent strain, the envA mutant was found to be more resistant to ultraviolet irradiation on plates. Prestarvation for tryptophan had a protective effect against irradiation both on the parent strain and the envA mutant. Images PMID:4887513

  20. Synergistic antibacterial activity of Curcumin with antibiotics against Staphylococcus aureus.

    PubMed

    Teow, Sin-Yeang; Ali, Syed Atif

    2015-11-01

    This study evaluated the synergistic antibacterial activity of Curcumin with 8 different antibiotic groups. Two reference, one clinical and ten environmental strains of Staphylococcus aureus (S. aureus) were tested. Disc diffusion assay with 25 μg/mL Curcumin demonstrated synergism in combination with a majority of tested antibiotics against S. aureus. However, checkerboard micro dilution assay only showed synergism, fractional inhibitory concentration index (FICI) <0.5 in three antibiotics i.e. Gentamicin, Amikacin, and Ciprofloxacin. Other antibiotics showed indifferent interactions but no antagonism was observed. In time-kill curve, appreciable reduction of bacterial cells was also observed in combination therapy (Curcumin + antibiotics) compared to monotherapy (Curcumin or antibiotic(s) alone). The antibiotics with higher synergistic interaction with Curcumin are arranged in a decreasing order: Amikacin > Gentamicin > Ciprofloxacin.

  1. Antibiotic efficacy is linked to bacterial cellular respiration

    PubMed Central

    Lobritz, Michael A.; Belenky, Peter; Porter, Caroline B. M.; Gutierrez, Arnaud; Yang, Jason H.; Schwarz, Eric G.; Dwyer, Daniel J.; Khalil, Ahmad S.; Collins, James J.

    2015-01-01

    Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes—the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy. PMID:26100898

  2. Predation and selection for antibiotic resistance in natural environments.

    PubMed

    Leisner, Jørgen J; Jørgensen, Niels O G; Middelboe, Mathias

    2016-03-01

    Genes encoding resistance to antibiotics appear, like the antibiotics themselves, to be ancient, originating long before the rise of the era of anthropogenic antibiotics. However, detailed understanding of the specific biological advantages of antibiotic resistance in natural environments is still lacking, thus limiting our efforts to prevent environmental influx of resistance genes. Here, we propose that antibiotic-resistant cells not only evade predation from antibiotic producers but also take advantage of nutrients released from cells that are killed by the antibiotic-producing bacteria. Thus, predation is potentially an important mechanism for driving antibiotic resistance during slow or stationary phase of growth when nutrients are deprived. This adds to explain the ancient nature and widespread occurrence of antibiotic resistance in natural environments unaffected by anthropogenic antibiotics. In particular, we suggest that nutrient-poor environments including indoor environments, for example, clean rooms and intensive care units may serve as a reservoir and source for antibiotic-producing as well as antibiotic-resistant bacteria.

  3. Antibiotic efficacy is linked to bacterial cellular respiration.

    PubMed

    Lobritz, Michael A; Belenky, Peter; Porter, Caroline B M; Gutierrez, Arnaud; Yang, Jason H; Schwarz, Eric G; Dwyer, Daniel J; Khalil, Ahmad S; Collins, James J

    2015-07-01

    Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes--the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy.

  4. Ribosomal Antibiotics: Contemporary Challenges.

    PubMed

    Auerbach-Nevo, Tamar; Baram, David; Bashan, Anat; Belousoff, Matthew; Breiner, Elinor; Davidovich, Chen; Cimicata, Giuseppe; Eyal, Zohar; Halfon, Yehuda; Krupkin, Miri; Matzov, Donna; Metz, Markus; Rufayda, Mruwat; Peretz, Moshe; Pick, Ophir; Pyetan, Erez; Rozenberg, Haim; Shalev-Benami, Moran; Wekselman, Itai; Zarivach, Raz; Zimmerman, Ella; Assis, Nofar; Bloch, Joel; Israeli, Hadar; Kalaora, Rinat; Lim, Lisha; Sade-Falk, Ofir; Shapira, Tal; Taha-Salaime, Leena; Tang, Hua; Yonath, Ada

    2016-06-29

    Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of "pathogen-specific antibiotics," in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification.

  5. Ribosomal Antibiotics: Contemporary Challenges.

    PubMed

    Auerbach-Nevo, Tamar; Baram, David; Bashan, Anat; Belousoff, Matthew; Breiner, Elinor; Davidovich, Chen; Cimicata, Giuseppe; Eyal, Zohar; Halfon, Yehuda; Krupkin, Miri; Matzov, Donna; Metz, Markus; Rufayda, Mruwat; Peretz, Moshe; Pick, Ophir; Pyetan, Erez; Rozenberg, Haim; Shalev-Benami, Moran; Wekselman, Itai; Zarivach, Raz; Zimmerman, Ella; Assis, Nofar; Bloch, Joel; Israeli, Hadar; Kalaora, Rinat; Lim, Lisha; Sade-Falk, Ofir; Shapira, Tal; Taha-Salaime, Leena; Tang, Hua; Yonath, Ada

    2016-01-01

    Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of "pathogen-specific antibiotics," in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification. PMID:27367739

  6. Ribosomal Antibiotics: Contemporary Challenges

    PubMed Central

    Auerbach-Nevo, Tamar; Baram, David; Bashan, Anat; Belousoff, Matthew; Breiner, Elinor; Davidovich, Chen; Cimicata, Giuseppe; Eyal, Zohar; Halfon, Yehuda; Krupkin, Miri; Matzov, Donna; Metz, Markus; Rufayda, Mruwat; Peretz, Moshe; Pick, Ophir; Pyetan, Erez; Rozenberg, Haim; Shalev-Benami, Moran; Wekselman, Itai; Zarivach, Raz; Zimmerman, Ella; Assis, Nofar; Bloch, Joel; Israeli, Hadar; Kalaora, Rinat; Lim, Lisha; Sade-Falk, Ofir; Shapira, Tal; Taha-Salaime, Leena; Tang, Hua; Yonath, Ada

    2016-01-01

    Most ribosomal antibiotics obstruct distinct ribosomal functions. In selected cases, in addition to paralyzing vital ribosomal tasks, some ribosomal antibiotics are involved in cellular regulation. Owing to the global rapid increase in the appearance of multi-drug resistance in pathogenic bacterial strains, and to the extremely slow progress in developing new antibiotics worldwide, it seems that, in addition to the traditional attempts at improving current antibiotics and the intensive screening for additional natural compounds, this field should undergo substantial conceptual revision. Here, we highlight several contemporary issues, including challenging the common preference of broad-range antibiotics; the marginal attention to alterations in the microbiome population resulting from antibiotics usage, and the insufficient awareness of ecological and environmental aspects of antibiotics usage. We also highlight recent advances in the identification of species-specific structural motifs that may be exploited for the design and the creation of novel, environmental friendly, degradable, antibiotic types, with a better distinction between pathogens and useful bacterial species in the microbiome. Thus, these studies are leading towards the design of “pathogen-specific antibiotics,” in contrast to the current preference of broad range antibiotics, partially because it requires significant efforts in speeding up the discovery of the unique species motifs as well as the clinical pathogen identification. PMID:27367739

  7. Staphylococcus aureus persisters tolerant to bactericidal antibiotics

    PubMed Central

    Lechner, Sabrina; Lewis, Kim; Bertram, Ralph

    2012-01-01

    Bacterial persister cells are non- or slow growing reversible phenotypic variants of the wild type, tolerant to bactericidal antibiotics. We here analyzed Staphylococcus aureus persister levels by monitoring colony forming unit (CFU) counts of planktonically grown cells treated with six different antimicrobials over time. Model laboratory strains HG001-HG003, SA113 and small colony variant (SCV) strains hemB and menD were challenged by the compounds at different logs of minimal inhibitory concentration (MIC) in exponential or stationary growth phase. Antibiotic tolerance was usually elevated in SCV strains compared to normally growing cells and in stationary vs. exponential phase cultures. Biphasic killing kinetics, typical for persister cell enrichment, were observed in both growth phases under different selective conditions. Treatment of exponential phase cultures of HG001-HG003 with 10-fold MIC of tobramycin resulted in the isolation of persisters which upon cultivation on plates formed either normal or phenotypically stable small colonies. Trajectories of different killing curves indicated physiological heterogeneity within persister subpopulations. Daptomycin added at 100-fold MIC to stationary phase SA113 cells rapidly isolated very robust persisters. Fractions of antibiotic tolerant cells were observed with all S. aureus strains and mutants tested. Our results refute the hypothesis that S. aureus stationary phase cells are equivalent to persisters, as not all of these cells showed antibiotic tolerance. Isolation of S. aureus persisters of different robustness seems to dependent on the kind and concentration of the antibiotic, as well as on the strain used. PMID:22986269

  8. Two Small RNAs Conserved in Enterobacteriaceae Provide Intrinsic Resistance to Antibiotics Targeting the Cell Wall Biosynthesis Enzyme Glucosamine-6-Phosphate Synthase.

    PubMed

    Khan, Muna A; Göpel, Yvonne; Milewski, Slawomir; Görke, Boris

    2016-01-01

    Formation of glucosamine-6-phosphate (GlcN6P) by enzyme GlcN6P synthase (GlmS) represents the first step in bacterial cell envelope synthesis. In Escherichia coli, expression of glmS is controlled by small RNAs (sRNAs) GlmY and GlmZ. GlmZ activates the glmS mRNA by base-pairing. When not required, GlmZ is bound by adapter protein RapZ and recruited to cleavage by RNase E inactivating the sRNA. The homologous sRNA GlmY activates glmS indirectly. When present at high levels, GlmY sequesters RapZ by an RNA mimicry mechanism suppressing cleavage of GlmZ. The interplay of both sRNAs is believed to adjust GlmS synthesis to the needs of the cell, i.e., to achieve GlcN6P homeostasis. Bacilysin (tetaine) and Nva-FMDP are dipeptide antibiotics that impair cell envelope synthesis by inhibition of enzyme GlmS through covalent modification. However, although taken up efficiently, these antibiotics are less active against E. coli for reasons unknown so far. Here we show that the GlmY/GlmZ circuit provides resistance. Inhibition of GlmS causes GlcN6P deprivation leading to activation of GlmY and GlmZ, which in turn trigger glmS overexpression in a dosage-dependent manner. Mutation of glmY or glmZ disables this response and renders the bacteria highly susceptible to GlmS inhibitors. Thus, E. coli compensates inhibition of GlmS by increasing its synthesis through the GlmY/GlmZ pathway. This mechanism is also operative in Salmonella indicating that it is conserved in Enterobacteriaceae possessing these sRNAs. As GlmY apparently responds to GlcN6P, co-application of a non-metabolizable GlcN6P analog may prevent activation of the sRNAs and thereby increase the bactericidal activity of GlmS inhibitors against wild-type bacteria. Initial experiments using glucosamine-6-sulfate support this possibility. Thus, GlcN6P analogs might be considered for co-application with GlmS inhibitors in combined therapy to treat infections caused by pathogenic Enterobacteriaceae. PMID:27379045

  9. Two Small RNAs Conserved in Enterobacteriaceae Provide Intrinsic Resistance to Antibiotics Targeting the Cell Wall Biosynthesis Enzyme Glucosamine-6-Phosphate Synthase

    PubMed Central

    Khan, Muna A.; Göpel, Yvonne; Milewski, Slawomir; Görke, Boris

    2016-01-01

    Formation of glucosamine-6-phosphate (GlcN6P) by enzyme GlcN6P synthase (GlmS) represents the first step in bacterial cell envelope synthesis. In Escherichia coli, expression of glmS is controlled by small RNAs (sRNAs) GlmY and GlmZ. GlmZ activates the glmS mRNA by base-pairing. When not required, GlmZ is bound by adapter protein RapZ and recruited to cleavage by RNase E inactivating the sRNA. The homologous sRNA GlmY activates glmS indirectly. When present at high levels, GlmY sequesters RapZ by an RNA mimicry mechanism suppressing cleavage of GlmZ. The interplay of both sRNAs is believed to adjust GlmS synthesis to the needs of the cell, i.e., to achieve GlcN6P homeostasis. Bacilysin (tetaine) and Nva-FMDP are dipeptide antibiotics that impair cell envelope synthesis by inhibition of enzyme GlmS through covalent modification. However, although taken up efficiently, these antibiotics are less active against E. coli for reasons unknown so far. Here we show that the GlmY/GlmZ circuit provides resistance. Inhibition of GlmS causes GlcN6P deprivation leading to activation of GlmY and GlmZ, which in turn trigger glmS overexpression in a dosage-dependent manner. Mutation of glmY or glmZ disables this response and renders the bacteria highly susceptible to GlmS inhibitors. Thus, E. coli compensates inhibition of GlmS by increasing its synthesis through the GlmY/GlmZ pathway. This mechanism is also operative in Salmonella indicating that it is conserved in Enterobacteriaceae possessing these sRNAs. As GlmY apparently responds to GlcN6P, co-application of a non-metabolizable GlcN6P analog may prevent activation of the sRNAs and thereby increase the bactericidal activity of GlmS inhibitors against wild-type bacteria. Initial experiments using glucosamine-6-sulfate support this possibility. Thus, GlcN6P analogs might be considered for co-application with GlmS inhibitors in combined therapy to treat infections caused by pathogenic Enterobacteriaceae. PMID:27379045

  10. Antibiotic resistance shaping multi-level population biology of bacteria

    PubMed Central

    Baquero, Fernando; Tedim, Ana P.; Coque, Teresa M.

    2013-01-01

    Antibiotics have natural functions, mostly involving cell-to-cell signaling networks. The anthropogenic production of antibiotics, and its release in the microbiosphere results in a disturbance of these networks, antibiotic resistance tending to preserve its integrity. The cost of such adaptation is the emergence and dissemination of antibiotic resistance genes, and of all genetic and cellular vehicles in which these genes are located. Selection of the combinations of the different evolutionary units (genes, integrons, transposons, plasmids, cells, communities and microbiomes, hosts) is highly asymmetrical. Each unit of selection is a self-interested entity, exploiting the higher hierarchical unit for its own benefit, but in doing so the higher hierarchical unit might acquire critical traits for its spread because of the exploitation of the lower hierarchical unit. This interactive trade-off shapes the population biology of antibiotic resistance, a composed-complex array of the independent “population biologies.” Antibiotics modify the abundance and the interactive field of each of these units. Antibiotics increase the number and evolvability of “clinical” antibiotic resistance genes, but probably also many other genes with different primary functions but with a resistance phenotype present in the environmental resistome. Antibiotics influence the abundance, modularity, and spread of integrons, transposons, and plasmids, mostly acting on structures present before the antibiotic era. Antibiotics enrich particular bacterial lineages and clones and contribute to local clonalization processes. Antibiotics amplify particular genetic exchange communities sharing antibiotic resistance genes and platforms within microbiomes. In particular human or animal hosts, the microbiomic composition might facilitate the interactions between evolutionary units involved in antibiotic resistance. The understanding of antibiotic resistance implies expanding our knowledge on multi

  11. Bacterial Cheating Limits the Evolution of Antibiotic Resistance

    NASA Astrophysics Data System (ADS)

    Yurtsev, Eugene; Xiao Chao, Hui; Datta, Manoshi; Artemova, Tatiana; Gore, Jeff

    2012-02-01

    The emergence of antibiotic resistance in bacteria is a significant health concern. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removal of the antibiotic. The presence of a cooperative mechanism of resistance suggests that a cheater strain - which does not contribute to breaking down the antibiotic - may be able to take advantage of resistant cells. We find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We use a simple model in conjunction with difference equations to explain the observed population dynamics as a function of cell density and antibiotic concentration. Our experimental difference equations resemble the logistic map, raising the possibility of oscillations or even chaotic dynamics.

  12. Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria

    PubMed Central

    Bennett, P M

    2008-01-01

    Bacteria have existed on Earth for three billion years or so and have become adept at protecting themselves against toxic chemicals. Antibiotics have been in clinical use for a little more than 6 decades. That antibiotic resistance is now a major clinical problem all over the world attests to the success and speed of bacterial adaptation. Mechanisms of antibiotic resistance in bacteria are varied and include target protection, target substitution, antibiotic detoxification and block of intracellular antibiotic accumulation. Acquisition of genes needed to elaborate the various mechanisms is greatly aided by a variety of promiscuous gene transfer systems, such as bacterial conjugative plasmids, transposable elements and integron systems, that move genes from one DNA system to another and from one bacterial cell to another, not necessarily one related to the gene donor. Bacterial plasmids serve as the scaffold on which are assembled arrays of antibiotic resistance genes, by transposition (transposable elements and ISCR mediated transposition) and site-specific recombination mechanisms (integron gene cassettes). The evidence suggests that antibiotic resistance genes in human bacterial pathogens originate from a multitude of bacterial sources, indicating that the genomes of all bacteria can be considered as a single global gene pool into which most, if not all, bacteria can dip for genes necessary for survival. In terms of antibiotic resistance, plasmids serve a central role, as the vehicles for resistance gene capture and their subsequent dissemination. These various aspects of bacterial resistance to antibiotics will be explored in this presentation. PMID:18193080

  13. Coping with antibiotic resistance: combining nanoparticles with antibiotics and other antimicrobial agents.

    PubMed

    Allahverdiyev, Adil M; Kon, Kateryna Volodymyrivna; Abamor, Emrah Sefik; Bagirova, Malahat; Rafailovich, Miriam

    2011-11-01

    The worldwide escalation of bacterial resistance to conventional medical antibiotics is a serious concern for modern medicine. High prevalence of multidrug-resistant bacteria among bacteria-based infections decreases effectiveness of current treatments and causes thousands of deaths. New improvements in present methods and novel strategies are urgently needed to cope with this problem. Owing to their antibacterial activities, metallic nanoparticles represent an effective solution for overcoming bacterial resistance. However, metallic nanoparticles are toxic, which causes restrictions in their use. Recent studies have shown that combining nanoparticles with antibiotics not only reduces the toxicity of both agents towards human cells by decreasing the requirement for high dosages but also enhances their bactericidal properties. Combining antibiotics with nanoparticles also restores their ability to destroy bacteria that have acquired resistance to them. Furthermore, nanoparticles tagged with antibiotics have been shown to increase the concentration of antibiotics at the site of bacterium-antibiotic interaction, and to facilitate binding of antibiotics to bacteria. Likewise, combining nanoparticles with antimicrobial peptides and essential oils generates genuine synergy against bacterial resistance. In this article, we aim to summarize recent studies on interactions between nanoparticles and antibiotics, as well as other antibacterial agents to formulate new prospects for future studies. Based on the promising data that demonstrated the synergistic effects of antimicrobial agents with nanoparticles, we believe that this combination is a potential candidate for more research into treatments for antibiotic-resistant bacteria.

  14. Antibiotics and production of granulocyte-macrophage colony-stimulating factor by human bronchial epithelial cells in vitro. A comparison of cefodizime and ceftriaxone.

    PubMed

    Pacheco, Y; Hosni, R; Dagrosa, E E; Gormand, F; Guibert, B; Chabannes, B; Lagarde, M; Perrin-Fayolle, M

    1994-04-01

    Cultured human bronchial epithelial cells (HBEC) produce both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 8 (IL-8). The influence of cefodizime (CAS 69739-16-8), a new broad spectrum cephalosporin with immunostimulatory effects, and ceftriaxone on the production of GM-CSF and IL-8 in HBEC primary cultures was investigated. HBEC were isolated from biopsy specimens obtained during fibreoptic bronchoscopy in 12 patients (most frequent diagnosis: chronic bronchitis). Confluent monolayers of HBEC cultured on collagen were incubated for 24 h in a medium without study drugs (spontaneous production) or containing cefodizime or ceftriaxone at the clinically relevant concentrations of 1, 10 and 100 mg/l, with or without tumor necrosis factor alpha (TNF alpha, 100 U/ml). GM-CSF and IL-8 were measured in supernatant by ELISA technique. TNF alpha alone led to a significant (p < 0.005) increase in both GM-CSF and IL-8 production. Cefodizime induced a significant (p < 0.05), dose-dependent increase in GM-CSF release. No additive effect of cefodizime with TNF alpha was observed. Cefodizime did not affect IL-8 production and ceftriaxone had no influence on cytokine production. This is the first report of a stimulatory effect of a beta-lactam antibiotic on cytokine production by epithelial cells. GM-CSF production by epithelial cells is an important immunological step for neutrophil and monocyte recruitment and cell priming during lung defence. Previous studies with cefodizime in immunodepressed subjects have shown activation of phagocytosis and phagocytosis-related functions in non-lung phagocytes. An indirect mechanism of action, similar to that indicated by our results, may have been responsible for these stimulatory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. [Determination of antibiotics using luminescent Escherichia coli and serum].

    PubMed

    Vlasova, I I; Asrieli, T V; Gavrilova, E M; Danilov, V S

    2007-01-01

    The methodical bases for detecting antibiotics using a bioluminescent assay and blood serum are briefed. Antibiotics inhibit the luminescence of a genetically engineered Escherichia coli strain. The degree of inhibition depended on the type of antibiotic, its concentration, and the time of cell incubation with antibiotic. The highest cell sensitivity was recorded towards the aminoglycoside antibiotics, which amounted to 85 +/- 10 ng/ml for gentamicin and streptomycin. The sensitivity of this system to a number of antibiotics essentially increased when the cells were previously activated with blood serum. The sensitivity of this method for gentamicin and streptomycin in the presence of blood serum amounted to 2.5 +/- 0.5 ng/ml; for tetracycline, 45 +/- 8 ng/ml. Use of the sera containing specific antibodies to the antibiotic detected provided a high sensitivity of the biosensor tested. Comparison of the luminescences of E. coli cells activated with normal and specific antisera upon incubation with an antibiotic allows the type of antibiotic and its quantitative content in the sample to be determined. Characteristic of the analysis of antibiotics with the help of recombinant E. coli are a high accuracy, sensitivity, specificity, simplicity, and a short time needed for measurement.

  16. Setamycin, a new antibiotic.

    PubMed

    Omura, S; Otoguro, K; Nishikiori, T; Oiwa, R; Iwai, Y

    1981-10-01

    A new antibiotic, setamycin, was extracted from the mycelia of a rare actinomycete strain KM-6054. The antibiotic, the molecular formula of which was found to be C42H61NO12 (tentative), is a yellow powder showing activity against some fungi, trichomonads and weakly against Gram-positive bacteria. PMID:7309621

  17. Antibiotic-Resistant Bacteria.

    ERIC Educational Resources Information Center

    Longenecker, Nevin E.; Oppenheimer, Dan

    1982-01-01

    A study conducted by high school advanced bacteriology students appears to confirm the hypothesis that the incremental administration of antibiotics on several species of bacteria (Escherichia coli, Staphylococcus epidermis, Bacillus sublitus, Bacillus megaterium) will allow for the development of antibiotic-resistant strains. (PEB)

  18. [Antibiotics: present and future].

    PubMed

    Bérdy, János

    2013-04-14

    The author discuss the up to date interpretation of the concept of antibiotics and antibiotic research, as well as the present role of various natural, semisynthetic and synthetic antibiotic compounds in various areas of the human therapy. The origin and the total number of all antibiotics and applied antibiotics in the practice, as well as the bioactive microbial metabolites (antibiotics) in other therapeutical, non-antibiotic fields (including agriculture) are also reviewed. The author discusses main problems, such as increasing (poly)resistance, virulence of pathogens and the non-scientific factors (such as a decline of research efforts and their sociological, economic, financial and regulatory reasons). A short summary of the history of Hungarian antibiotic research is also provided. The author briefly discusses the prospects in the future and the general advantages of the natural products over synthetic compounds. It is concluded that new approaches for the investigation of the unlimited possibilities of the living world are necessary. The discovery of new types or simply neglected (micro)organisms and their biosynthetic capabilities, the introduction of new biotechnological and genetic methods (genomics, metagenom, genome mining) are absolutely required in the future.

  19. BMAP-28, an Antibiotic Peptide of Innate Immunity, Induces Cell Death through Opening of the Mitochondrial Permeability Transition Pore

    PubMed Central

    Risso, Angela; Braidot, Enrico; Sordano, Maria Concetta; Vianello, Angelo; Macrì, Francesco; Skerlavaj, Barbara; Zanetti, Margherita; Gennaro, Renato; Bernardi, Paolo

    2002-01-01

    BMAP-28, a bovine antimicrobial peptide of the cathelicidin family, induces membrane permeabilization and death in human tumor cell lines and in activated, but not resting, human lymphocytes. In addition, we found that BMAP-28 causes depolarization of the inner mitochondrial membrane in single cells and in isolated mitochondria. The effect of the peptide was synergistic with that of Ca2+ and inhibited by cyclosporine, suggesting that depolarization depends on opening of the mitochondrial permeability transition pore. The occurrence of a permeability transition was investigated on the basis of mitochondrial permeabilization to calcein and cytochrome c release. We show that BMAP-28 permeabilizes mitochondria to entrapped calcein in a cyclosporine-sensitive manner and that it releases cytochrome c in situ. Our results demonstrate that BMAP-28 is an inducer of the mitochondrial permeability transition pore and that its cytotoxic potential depends on its effects on mitochondrial permeability. PMID:11865069

  20. Metagenomics and antibiotics.

    PubMed

    Garmendia, L; Hernandez, A; Sanchez, M B; Martinez, J L

    2012-07-01

    Most of the bacterial species that form part of the biosphere have never been cultivated. In this situation, a comprehensive study of bacterial communities requires the utilization of non-culture-based methods, which have been named metagenomics. In this paper we review the use of different metagenomic techniques for understanding the effect of antibiotics on microbial communities, to synthesize new antimicrobial compounds and to analyse the distribution of antibiotic resistance genes in different ecosystems. These techniques include functional metagenomics, which serves to find new antibiotics or new antibiotic resistance genes, and descriptive metagenomics, which serves to analyse changes in the composition of the microbiota and to track the presence and abundance of already known antibiotic resistance genes in different ecosystems.

  1. Septum Formation in Escherichia coli: Characterization of Septal Structure and the Effects of Antibiotics on Cell Division

    PubMed Central

    Burdett, I. D. J.; Murray, R. G. E.

    1974-01-01

    Septa can be demonstrated in sections of Escherichia coli strains B and B/r after fixation with acrolein and glutaraldehyde. The septum consists of an ingrowth of the cytoplasmic membrane and the mucopeptide layer; the outer membrane is excluded from the septum until the cells begin to separate. Mesosomes have also been observed. The septum is highly labile and, except in the chain-forming strains, E. coli D22 env A and CRT 97, not easily preserved by standard procedures. The labile nature of the septum may be due to the presence of autolysin(s) located at the presumptive division site. Blocking division by addition of ampicillin (2 to 5 μg/ml) to cells of E. coli B/r produces a bulge at the middle of the cells; bulge formation is stopped by addition of chloramphenicol. Cephalosporins also induce bulge formation but may stop cell elongation as well as division. Bulge formation, due to the presumed action of an autolysin(s), may be an initial step in the septation sequence when the mucopeptide is modified to allow construction of the septum. In a nonseptate filament-forming strain, PAT 84, which ceases to divide at 42 C, bulge formation only occurs in the presence of ampicillin at the time of a shift-down at 30 C or at 42 C in the presence of NaCl (0.25 to 0.34 M). Experiments with chloramphenicol suggest that the filaments are fully compartmentalized but fail to divide owing to the inactivation, rather than loss of synthesis, of an autolysin at 42 C. Images PMID:4209778

  2. Antibiotic-loaded chitosan-Laponite films for local drug delivery by titanium implants: cell proliferation and drug release studies.

    PubMed

    Ordikhani, Farideh; Dehghani, Mehdi; Simchi, Arash

    2015-12-01

    In this study, chitosan-Laponite nanocomposite coatings with bone regenerative potential and controlled drug-release capacity are prepared by electrophoretic deposition technique. The controlled release of a glycopeptide drug, i.e. vancomycin, is attained by the intercalation of the polymer and drug macromolecules into silicate galleries. Fourier-transform infrared spectrometry reveals electrostatic interactions between the charged structure of clay and the amine and hydroxyl groups of chitosan and vancomycin, leading to a complex positively-charged system with high electrophoretic mobility. By applying electric field the charged particles are deposited on the surface of titanium foils and uniform chitosan films containing 25-55 wt% Laponite and 937-1655 µg/cm(2) vancomycin are obtained. Nanocomposite films exhibit improved cell attachment with higher cell viability. Alkaline phosphatase assay reveals enhanced cell proliferation due the gradual dissolution of Laponite particles into the culture medium. In-vitro drug-release studies show lower release rate through a longer period for the nanocomposite compared to pristine chitosan. PMID:26507202

  3. In vitro activities of native and designed peptide antibiotics against drug sensitive and resistant tumor cell lines.

    PubMed

    Kim, Sunkyu; Kim, Sukwon S; Bang, Yung Jue; Kim, Seong Jin; Lee, Byeong Jae

    2003-07-01

    In order to develop peptide agents with reduced length and enhanced tumoricidal activity, we have designed gaegurin 6 (GGN6) derivatives through deletions and/or substitutions of amino acids. The deletion of hydrophobic amino terminal region completely abolished antitumor activity whereas the deletion of carboxy terminal region had little influence on antitumor activity. Antitumor activity of the PTP peptides did not correlate with antibacterial activity. PTP7, the most potent derivative, was found to have comparable antitumor activity to GGN6 in spite of reduced number of amino acids which is about half the size of gaegurin 6; furthermore, it showed little cytotoxicity on PBMCs and RBCs. GGN6 and PTP7 also showed equivalent cytotoxicity against drug sensitive (MCF-7) and multidrug-resistant cell lines (MCF-7/DOX). Plasma membrane blebbing and DNA fragmentation of peptide-treated tumor cells indicated that the peptides could induce apoptosis in tumor cells. These results suggest that GGN6 and its derivatives can be developed as new anticancer agents and may provide a new strategy for overcoming MDR which is a major problem in cancer therapy.

  4. Restoration of susceptibility of intracellular methicillin-resistant Staphylococcus aureus to beta-lactams: comparison of strains, cells, and antibiotics.

    PubMed

    Lemaire, Sandrine; Olivier, Aurélie; Van Bambeke, Françoise; Tulkens, Paul M; Appelbaum, Peter C; Glupczynski, Youri

    2008-08-01

    Staphylococcus aureus invades eukaryotic cells. When methicillin-resistant S. aureus (MRSA) ATCC 33591 is phagocytized by human THP-1 macrophages, complete restoration of susceptibility to cloxacillin and meropenem is shown and the strain becomes indistinguishable from MSSA ATCC 25923 due to the acid pH prevailing in phagolysosomes (S. Lemaire et al., Antimicrob. Agents Chemother. 51:1627-1632, 2007). We examined whether this observation can be extended to (i) strains of current clinical and epidemiological interest (three hospital-acquired MRSA [HA-MRSA] strains, two community-acquired MRSA [CA-MRSA] strains, two HA-MRSA strains with the vancomycin-intermediate phenotype, one HA-MRSA strain with the vancomycin-resistant phenotype, and one animal [porcine] MRSA strain), (ii) activated THP-1 cells and nonprofessional phagocytes (keratinocytes, Calu-3 bronchial epithelial cells), and (iii) other beta-lactams (imipenem, oxacillin, cefuroxime, cefepime). All strains showed (i) a marked reduction in MICs in broth at pH 5.5 compared with the MIC at pH 7.4 and (ii) sigmoidal dose-response curves with cloxacillin (0.01x to 100x MIC, 24 h of incubation) after phagocytosis by THP-1 macrophages that were indistinguishable from each other and from the dose-response curve for methicillin-susceptible S. aureus (MSSA) ATCC 25923 (relative potency [50% effect], 6.09x MIC [95% confidence interval {CI}, 4.50 to 8.25]; relative efficacy [change in bacterial counts over the original inoculum for an infinitely large cloxacillin concentration, or maximal effect], -0.69 log CFU [95% CI, -0.79 to -0.58]). Similar dose-response curves for cloxacillin were also observed with MSSA ATCC 25923 and MRSA ATCC 33591 after phagocytosis by activated THP-1 macrophages, keratinocytes, and Calu-3 cells. By contrast, there was a lower level of restoration of susceptibility of MRSA ATCC 33591 to cefuroxime and cefepime after phagocytosis by THP-1 macrophages, even when the data were normalized for

  5. Gut Check: IFNγ Delays Mucosal Recovery during Antibiotic Therapy.

    PubMed

    Chung, Lawton K; Bliska, James B

    2016-08-10

    Antibiotic therapy has been largely ineffective in improving clinical outcomes following Salmonellosis, yet the reasons why remain obscure. In this issue of Cell Host & Microbe, Dolowschiak et al. (2016) report that IFNγ produced by NK and T cells following antibiotic treatment of acute Salmonella infection limits mucosal remission. PMID:27512899

  6. Engineering persister-specific antibiotics with synergistic antimicrobial functions.

    PubMed

    Schmidt, Nathan W; Deshayes, Stephanie; Hawker, Sinead; Blacker, Alyssa; Kasko, Andrea M; Wong, Gerard C L

    2014-09-23

    Most antibiotics target growth processes and are ineffective against persister bacterial cells, which tolerate antibiotics due to their reduced metabolic activity. These persisters act as a genetic reservoir for resistant mutants and constitute a root cause of antibiotic resistance, a worldwide problem in human health. We re-engineer antibiotics specifically for persisters using tobramycin, an aminoglycoside antibiotic that targets bacterial ribosomes but is ineffective against persisters with low metabolic and cellular transport activity. By giving tobramycin the ability to induce nanoscopic negative Gaussian membrane curvature via addition of 12 amino acids, we transform tobramycin itself into a transporter sequence. The resulting molecule spontaneously permeates membranes, retains the high antibiotic activity of aminoglycosides, kills E. coli and S. aureus persisters 4-6 logs better than tobramycin, but remains noncytotoxic to eukaryotes. These results suggest a promising paradigm to renovate traditional antibiotics.

  7. Mechanisms of antibiotic resistance in enterococci

    PubMed Central

    Miller, William R; Munita, Jose M; Arias, Cesar A

    2015-01-01

    Multidrug-resistant (MDR) enterococci are important nosocomial pathogens and a growing clinical challenge. These organisms have developed resistance to virtually all antimicrobials currently used in clinical practice using a diverse number of genetic strategies. Due to this ability to recruit antibiotic resistance determinants, MDR enterococci display a wide repertoire of antibiotic resistance mechanisms including modification of drug targets, inactivation of therapeutic agents, overexpression of efflux pumps and a sophisticated cell envelope adaptive response that promotes survival in the human host and the nosocomial environment. MDR enterococci are well adapted to survive in the gastrointestinal tract and can become the dominant flora under antibiotic pressure, predisposing the severely ill and immunocompromised patient to invasive infections. A thorough understanding of the mechanisms underlying antibiotic resistance in enterococci is the first step for devising strategies to control the spread of these organisms and potentially establish novel therapeutic approaches. PMID:25199988

  8. Enhanced production of the nonribosomal peptide antibiotic valinomycin in Escherichia coli through small-scale high cell density fed-batch cultivation.

    PubMed

    Li, Jian; Jaitzig, Jennifer; Hillig, Friederike; Süssmuth, Roderich; Neubauer, Peter

    2014-01-01

    Nonribosomal peptides (NRPs), a large family of natural products, possess numerous pharmaceutically significant bioactivities. However, many native microbial producers of NRPs are not cultivable or have low production yields making mass production infeasible. The recombinant production of natural products in a surrogate host has emerged as a strategy to overcome these limitations. De novo recombinant production of the NRP antibiotic valinomycin in an engineered Escherichia coli host strain was established with the necessary biosynthetic pathway constituents from Streptomyces tsusimaensis. In the present study, the initially modest valinomycin yields could be significantly increased from 0.3 up to 2.4 mg L⁻¹ by switching from a batch to an enzyme-based fed-batch mode in shake flasks. A subsequent design of experiment-driven optimization of parallel fed-batch cultivations in 24-well plates with online monitoring of dissolved oxygen and pH led to valinomycin yields up to 6.4 mg L⁻¹. Finally, repeated glucose polymer feeding to enzyme-based high cell density cultivations in shake flasks resulted in cell densities of OD₆₀₀>50 and a valinomycin titer of appr. 10 mg L⁻¹. This represents a 33-fold improvement compared to the initial batch cultivations and is the highest concentration of a nonribosomal peptide which has been produced in E. coli without feeding of specific precursors so far to our knowledge. Also, such a small-scale optimization under fed-batch conditions may be generally applicable for the development and scale-up of natural product production processes in E. coli.

  9. Sodium alginate-cross-linked polymyxin B sulphate-loaded solid lipid nanoparticles: Antibiotic resistance tests and HaCat and NIH/3T3 cell viability studies.

    PubMed

    Severino, Patrícia; Chaud, Marco V; Shimojo, Andrea; Antonini, Danilo; Lancelloti, Marcelo; Santana, Maria Helena A; Souto, Eliana B

    2015-05-01

    Polymyxins are a group of antibiotics with a common structure of a cyclic peptide with a long hydrophobic tail. Polymyxin B sulphate (PLX) has cationic charge, which is an obstacle for the efficient loading into Solid Lipid Nanoparticles (SLN). In the present paper, we describe an innovative method to load PLX into SLN to achieve the sustained release of the drug. PLX was firstly cross-linked with sodium alginate (SA) at different ratios (1:1, 1:2 and 1:3 SA/PLX), and loaded into SLN produced by high pressure homogenization (HPH). Optimized SLN were produced applying 500bar pressure and 5 homogenization cycles. The best results were obtained with SA/PLX (1:1), recording 99.08±1.2% for the association efficiency of the drug with SA, 0.99±10g for the loading capacity and 212.07±5.84% degree of swelling. The rheological profile of aqueous SA solution followed the typical behaviour of concentrated polymeric solutions, whereas aqueous SA/PLX solution exhibited a gel-like dynamic behaviour. Micrographs show that SA/PLX depicted a porous and discontinuous amorphous phase in different ratios. The encapsulation efficiency of SA/PLX (1:1) in SLN, the mean particle diameter, polydispersity index and zeta potential were, respectively, 82.7±5.5%; 439.5±20.42nm, 0.241±0.050 and -34.8±0.55mV. The effect of SLN on cell viability was checked in HaCat and NIH/3T3 cell lines, and the minimal inhibitory concentrations (MIC) were determined in Pseudomonas aeruginosa strains. SA/PLX-loaded SLN were shown to be less toxic than free PLX. Minimal inhibitory concentrations (MIC) showed the presence of the cross-linker polymer-drug complex, and SLN were shown to enhance MIC in the evaluated strains.

  10. Solving the Antibiotic Crisis.

    PubMed

    Wright, Gerard D

    2015-02-13

    Antibiotics are essential for both treating and preventing infectious diseases. Paradoxically, despite their importance as pillars of modern medicine, we are in danger of losing antibiotics because of the evolution and dissemination of resistance mechanisms throughout all pathogenic microbes. This fact, coupled with an inability to bring new drugs to market at a pace that matches resistance, has resulted in a crisis of global proportion. Solving this crisis requires the actions of many stakeholders, but chemists, chemical biologists, and microbiologists must drive the scientific innovation that is required to maintain our antibiotic arsenal. This innovation requires (1) a deep understanding of the evolution and reservoirs of resistance; (2) full knowledge of the molecular mechanisms of antibiotic action and resistance; (3) the discovery of chemical and genetic probes of antibiotic action and resistance; (4) the integration of systems biology into antibiotic discovery; and (5) the discovery of new antimicrobial chemical matter. Addressing these pressing scientific gaps will ensure that we can meet the antibiotic crisis with creativity and purpose. PMID:27622298

  11. Fighting antibiotic resistance in the intensive care unit using antibiotics.

    PubMed

    Plantinga, Nienke L; Wittekamp, Bastiaan H J; van Duijn, Pleun J; Bonten, Marc J M

    2015-01-01

    Antibiotic resistance is a global and increasing problem that is not counterbalanced by the development of new therapeutic agents. The prevalence of antibiotic resistance is especially high in intensive care units with frequently reported outbreaks of multidrug-resistant organisms. In addition to classical infection prevention protocols and surveillance programs, counterintuitive interventions, such as selective decontamination with antibiotics and antibiotic rotation have been applied and investigated to control the emergence of antibiotic resistance. This review provides an overview of selective oropharyngeal and digestive tract decontamination, decolonization of methicillin-resistant Staphylococcus aureus and antibiotic rotation as strategies to modulate antibiotic resistance in the intensive care unit.

  12. Antibiotic resistance in Burkholderia species.

    PubMed

    Rhodes, Katherine A; Schweizer, Herbert P

    2016-09-01

    The genus Burkholderia comprises metabolically diverse and adaptable Gram-negative bacteria, which thrive in often adversarial environments. A few members of the genus are prominent opportunistic pathogens. These include Burkholderia mallei and Burkholderia pseudomallei of the B. pseudomallei complex, which cause glanders and melioidosis, respectively. Burkholderia cenocepacia, Burkholderia multivorans, and Burkholderia vietnamiensis belong to the Burkholderia cepacia complex and affect mostly cystic fibrosis patients. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. The first line of defense against antimicrobials in Burkholderia species is the outer membrane penetration barrier. Most Burkholderia contain a modified lipopolysaccharide that causes intrinsic polymyxin resistance. Contributing to reduced drug penetration are restrictive porin proteins. Efflux pumps of the resistance nodulation cell division family are major players in Burkholderia multidrug resistance. Third and fourth generation β-lactam antibiotics are seminal for treatment of Burkholderia infections, but therapeutic efficacy is compromised by expression of several β-lactamases and ceftazidime target mutations. Altered DNA gyrase and dihydrofolate reductase targets cause fluoroquinolone and trimethoprim resistance, respectively. Although antibiotic resistance hampers therapy of Burkholderia infections, the characterization of resistance mechanisms lags behind other non-enteric Gram-negative pathogens, especially ESKAPE bacteria such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. PMID:27620956

  13. Resistance-resistant antibiotics.

    PubMed

    Oldfield, Eric; Feng, Xinxin

    2014-12-01

    New antibiotics are needed because drug resistance is increasing while the introduction of new antibiotics is decreasing. We discuss here six possible approaches to develop 'resistance-resistant' antibiotics. First, multitarget inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy owing to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, repurposing existing drugs can lead to combinations of multitarget therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and, in some cases, suggest that sensitivity to existing antibiotics may be restored in otherwise drug-resistant organisms.

  14. Antibiotic / Antimicrobial Resistance Glossary

    MedlinePlus

    ... on the Farm Get Smart About Antibiotics Week File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  15. Targeting Antibiotic Resistance

    PubMed Central

    Chellat, Mathieu F.; Raguž, Luka

    2016-01-01

    Abstract Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens. PMID:27000559

  16. [Antibiotic therapy in psittacines].

    PubMed

    Krautwald, M E

    1989-01-01

    The use of different antibiotics in psittacines is described. Among other aspects especially the anatomy of the bird and its consequence for the application of medicaments is taken into account. The use of antibiotics in psittacines often turns out to be difficult because of missing data about their pharmacokinetics, dosage, period of application and their compatibility. In order to deal with the increasing number of pet-birds in the veterinary practice, further examinations have to be conducted. PMID:2655172

  17. [The history of antibiotics].

    PubMed

    Yazdankhah, Siamak; Lassen, Jørgen; Midtvedt, Tore; Solberg, Claus Ola

    2013-12-10

    The development of chemical compounds for the treatment of infectious diseases may be divided into three phases: a) the discovery in the 1600s in South America of alkaloid extracts from the bark of the cinchona tree and from the dried root of the ipecacuanha bush, which proved effective against, respectively, malaria (quinine) and amoebic dysentery (emetine); b) the development of synthetic drugs, which mostly took place in Germany, starting with Paul Ehrlich's (1854-1915) discovery of salvarsan (1909), and crowned with Gerhard Domagk's (1895-1964) discovery of the sulfonamides (1930s); and c) the discovery of antibiotics. The prime example of the latter is the development of penicillin in the late 1920s following a discovery by a solitary research scientist who never worked in a team and never as part of a research programme. It took another ten years or so before drug-quality penicillin was produced, with research now dependent on being conducted in large collaborative teams, frequently between universities and wealthy industrial companies. The search for new antibiotics began in earnest in the latter half of the 1940s and was mostly based on soil microorganisms. Many new antibiotics were discovered in this period, which may be termed «the golden age of antibiotics». Over the past three decades, the development of new antibiotics has largely stalled, while antibiotic resistance has increased. This situation may require new strategies for the treatment of infectious diseases. PMID:24326504

  18. [The history of antibiotics].

    PubMed

    Yazdankhah, Siamak; Lassen, Jørgen; Midtvedt, Tore; Solberg, Claus Ola

    2013-12-10

    The development of chemical compounds for the treatment of infectious diseases may be divided into three phases: a) the discovery in the 1600s in South America of alkaloid extracts from the bark of the cinchona tree and from the dried root of the ipecacuanha bush, which proved effective against, respectively, malaria (quinine) and amoebic dysentery (emetine); b) the development of synthetic drugs, which mostly took place in Germany, starting with Paul Ehrlich's (1854-1915) discovery of salvarsan (1909), and crowned with Gerhard Domagk's (1895-1964) discovery of the sulfonamides (1930s); and c) the discovery of antibiotics. The prime example of the latter is the development of penicillin in the late 1920s following a discovery by a solitary research scientist who never worked in a team and never as part of a research programme. It took another ten years or so before drug-quality penicillin was produced, with research now dependent on being conducted in large collaborative teams, frequently between universities and wealthy industrial companies. The search for new antibiotics began in earnest in the latter half of the 1940s and was mostly based on soil microorganisms. Many new antibiotics were discovered in this period, which may be termed «the golden age of antibiotics». Over the past three decades, the development of new antibiotics has largely stalled, while antibiotic resistance has increased. This situation may require new strategies for the treatment of infectious diseases.

  19. Strategies to Minimize Antibiotic Resistance

    PubMed Central

    Lee, Chang-Ro; Cho, Ill Hwan; Jeong, Byeong Chul; Lee, Sang Hee

    2013-01-01

    Antibiotic resistance can be reduced by using antibiotics prudently based on guidelines of antimicrobial stewardship programs (ASPs) and various data such as pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics, diagnostic testing, antimicrobial susceptibility testing (AST), clinical response, and effects on the microbiota, as well as by new antibiotic developments. The controlled use of antibiotics in food animals is another cornerstone among efforts to reduce antibiotic resistance. All major resistance-control strategies recommend education for patients, children (e.g., through schools and day care), the public, and relevant healthcare professionals (e.g., primary-care physicians, pharmacists, and medical students) regarding unique features of bacterial infections and antibiotics, prudent antibiotic prescribing as a positive construct, and personal hygiene (e.g., handwashing). The problem of antibiotic resistance can be minimized only by concerted efforts of all members of society for ensuring the continued efficiency of antibiotics. PMID:24036486

  20. Auxotrophic markers pyrF and proC can replace antibiotic markers on protein production plasmids in high-cell-density Pseudomonas fluorescens fermentation.

    PubMed

    Schneider, Jane C; Jenings, Annika F; Mun, Deborah M; McGovern, Patricia M; Chew, Lawrence C

    2005-01-01

    The use of antibiotic-resistance genes as selectable markers in transgenic organisms is coming under increased scrutiny, for fear that they may spread to human pathogens, thereby reducing the effectiveness of antibiotic therapy. A current Pseudomonas fluorescens protein expression system uses a tetracycline resistance gene (tetR/tetA) to maintain an expression plasmid under control of a repressible promoter and a kanamycin resistance gene (kanR) to maintain a plasmid carrying a repressor gene. We investigated using auxotrophic markers to replace these two antibiotic resistance genes: pyrF (encoding orotidine-5'-phosphate decarboxylase) in place of tetR/tetA and proC (encoding pyrroline-5-carboxylate reductase) in place of kanR, complementing their respective precise chromosomal deletions created by allele exchange using a suicide vector carrying pyrF as a counterselectable marker. The resulting strains, devoid of antibiotic-resistance genes, were shown to achieve high productivity of nitrilase and thermostable alpha-amylase equal to that of the former antibiotic-resistant production host. The production plasmids were stable. The pyrF (uracil-dependent) background of the production host strain also allows us to sequentially alter the genome to incorporate other desired genomic changes, deletions, or insertions using 5'-fluoroorotic acid counterselection, restoring the selectable marker after each step.

  1. Do antibiotics clear bladder infections?

    PubMed

    Reid, G

    1994-09-01

    An examination of transitional bladder epithelial cells from 69 urine specimens from 23 spinal cord injury patients showed the presence of adherent bacterial biofilms in 66 cases (96%). All patients were receiving antimicrobial therapy, primarily trimethoprim-sulfamethoxazole (41 of 69), without any apparent effect on the bladder colonization. The large number of bacteria that emerged with highly virulent and potentially multi-drug resistant characteristics, especially Enterococcus faecalis (33% of isolates), was of concern. These findings raise questions about the proved efficacy and effectiveness of antibiotics against uropathogenic biofilms adherent to tissues.

  2. Staphylococcus aureus persisters tolerant to bactericidal antibiotics.

    PubMed

    Lechner, Sabrina; Lewis, Kim; Bertram, Ralph

    2012-01-01

    Bacterial persister cells are non- or slow-growing reversible phenotypic variants of the wild type, tolerant to bactericidal antibiotics. We analyzed here Staphylococcus aureus persister levels by monitoring colony-forming unit counts of planktonically grown cells treated with six different antimicrobials over time. The model laboratory strains HG001-HG003, SA113 and the small colony variant (SCV) strains hemB and menD were challenged by the compounds at different logs of minimal inhibitory concentration (MIC) in exponential or stationary growth phase. Antibiotic tolerance was usually elevated in SCV strains compared to normally growing cells and in stationary versus exponential phase cultures. Biphasic killing kinetics, typical for persister cell enrichment, were observed in both growth phases under different selective conditions. Treatment of exponential phase cultures of HG001-HG003 with 10-fold MIC of tobramycin resulted in the isolation of persisters which upon cultivation on plates formed either normal or phenotypically stable small colonies. Trajectories of different killing curves indicated physiological heterogeneity within persister subpopulations. Daptomycin added at 100-fold MIC to stationary phase SA113 cells rapidly isolated very robust persisters. Fractions of antibiotic-tolerant cells were observed with all S. aureus strains and mutants tested. Our results refute the hypothesis that S. aureus stationary phase cells are equivalent to persisters, as not all of these cells showed antibiotic tolerance. Isolation of S. aureus persisters of different robustness seems to depend on the kind and concentration of the antibiotic, as well as on the strain used. PMID:22986269

  3. Antibacterial compounds of Canadian honeys target bacterial cell wall inducing phenotype changes, growth inhibition and cell lysis that resemble action of β-lactam antibiotics.

    PubMed

    Brudzynski, Katrina; Sjaarda, Calvin

    2014-01-01

    Honeys show a desirable broad spectrum activity against Gram-positive and negative bacteria making antibacterial activity an intrinsic property of honey and a desirable source for new drug development. The cellular targets and underlying mechanism of action of honey antibacterial compounds remain largely unknown. To facilitate the target discovery, we employed a method of phenotypic profiling by directly comparing morphological changes in Escherichia coli induced by honeys to that of ampicillin, the cell wall-active β-lactam of known mechanism of action. Firstly, we demonstrated the purity of tested honeys from potential β-lactam contaminations using quantitative LC-ESI-MS. Exposure of log-phase E. coli to honey or ampicillin resulted in time- and concentration-dependent changes in bacterial cell shape with the appearance of filamentous phenotypes at sub-inhibitory concentrations and spheroplasts at the MBC. Cell wall destruction by both agents, clearly visible on microscopic micrographs, was accompanied by increased permeability of the lipopolysaccharide outer membrane as indicated by fluorescence-activated cell sorting (FACS). More than 90% E. coli exposed to honey or ampicillin became permeable to propidium iodide. Consistently with the FACS results, both honey-treated and ampicillin-treated E. coli cells released lipopolysaccharide endotoxins at comparable levels, which were significantly higher than controls (p<0.0001). E. coli cells transformed with the ampicillin-resistance gene (β-lactamase) remained sensitive to honey, displayed the same level of cytotoxicity, cell shape changes and endotoxin release as ampicillin-sensitive cells. As expected, β-lactamase protected the host cell from antibacterial action of ampicillin. Thus, both honey and ampicillin induced similar structural changes to the cell wall and LPS and that this ability underlies antibacterial activities of both agents. Since the cell wall is critical for cell growth and survival, honey

  4. Antibacterial compounds of Canadian honeys target bacterial cell wall inducing phenotype changes, growth inhibition and cell lysis that resemble action of β-lactam antibiotics.

    PubMed

    Brudzynski, Katrina; Sjaarda, Calvin

    2014-01-01

    Honeys show a desirable broad spectrum activity against Gram-positive and negative bacteria making antibacterial activity an intrinsic property of honey and a desirable source for new drug development. The cellular targets and underlying mechanism of action of honey antibacterial compounds remain largely unknown. To facilitate the target discovery, we employed a method of phenotypic profiling by directly comparing morphological changes in Escherichia coli induced by honeys to that of ampicillin, the cell wall-active β-lactam of known mechanism of action. Firstly, we demonstrated the purity of tested honeys from potential β-lactam contaminations using quantitative LC-ESI-MS. Exposure of log-phase E. coli to honey or ampicillin resulted in time- and concentration-dependent changes in bacterial cell shape with the appearance of filamentous phenotypes at sub-inhibitory concentrations and spheroplasts at the MBC. Cell wall destruction by both agents, clearly visible on microscopic micrographs, was accompanied by increased permeability of the lipopolysaccharide outer membrane as indicated by fluorescence-activated cell sorting (FACS). More than 90% E. coli exposed to honey or ampicillin became permeable to propidium iodide. Consistently with the FACS results, both honey-treated and ampicillin-treated E. coli cells released lipopolysaccharide endotoxins at comparable levels, which were significantly higher than controls (p<0.0001). E. coli cells transformed with the ampicillin-resistance gene (β-lactamase) remained sensitive to honey, displayed the same level of cytotoxicity, cell shape changes and endotoxin release as ampicillin-sensitive cells. As expected, β-lactamase protected the host cell from antibacterial action of ampicillin. Thus, both honey and ampicillin induced similar structural changes to the cell wall and LPS and that this ability underlies antibacterial activities of both agents. Since the cell wall is critical for cell growth and survival, honey

  5. Autolytic effect of the antibiotic produced by Myxococcus coralloides D.

    PubMed

    Montoya, M D; Gálvez, A; Arias, J M; Montoya, E

    1994-12-01

    Myxococcus coralloides D secretes an antibiotic, named corallolysin, when grown on a rich medium. When a critical concentration is reached, this antibiotic lyses the producer bacterium either during vegetative growth or during morphogenesis. Corallolysin has not effect on resting cells nor on myxospores. The autolytic effect is caused by the early inhibition of RNA synthesis.

  6. Clinical Characteristics Associated with Antibiotic Treatment Failure for Tuboovarian Abscesses

    PubMed Central

    Farid, Huma; Lau, Trevin C.; Karmon, Anatte E.; Styer, Aaron K.

    2016-01-01

    Objective. Although parenteral antibiotic treatment is a standard approach for tuboovarian abscesses, a significant proportion of patients fail therapy and require interventional radiology (IR) guided drainage. The objective of this study is to assess if specific clinical factors are associated with antibiotic treatment failure. Study Design. Retrospective medical record review of patients hospitalized for tuboovarian abscesses from 2001 through 2012 was performed. Clinical characteristics were compared for patients who underwent successful parenteral antibiotic treatment, failed antibiotic treatment necessitating subsequent IR drainage, initial drainage with concurrent antibiotics, and surgery. Results. One hundred thirteen patients admitted for inpatient treatment were identified. Sixty-one (54%) patients were treated with antibiotics alone. Within this group, 24.6% failed antibiotic treatment and required drainage. Mean white blood cell count (K/μL) (18.7 ± 5.94 versus 13.9 ± 5.12) (p = 0.003), mean maximum diameter of tuboovarian abscess (cm) (6.8 ± 2.9 versus 5.2 ± 2.0) (p = 0.03), and length of stay (days) (9.47 ± 7.43 versus 4.59 ± 2.4) (p = 0.002) were significantly greater for patients who failed antibiotic treatment. Conclusions. Admission white blood cell count greater than 16 K/μL and abscess size greater than 5.18 cm are associated with antibiotic treatment failure. These factors may provide guidance for initial selection of IR guided drainage. PMID:26989337

  7. [Sepsis management -- antibiotic therapy].

    PubMed

    Welte, T

    2004-11-26

    Sepsis is one of the most frequent infectious problems at Intensive Care Units, and sepsis is associated with significant mortality. The latter could not be markedly reduced in the last years, despite a number of advances in the field of volume substitution, catecholamines, and endocrinologic therapy. The reason might be that important steps towards overcoming of sepsis are the surgical resection of infectious foci and an adequate antibiotic treatment. A critical role plays the growing resistance of pathogens against the common antibiotics. Since no major progress in the development of new antibiotics can be expected for the next years, sepsis treatment must be focused on prevention of infection, and on an optimised application of current antibiotic substances. The key factors are a broad and high dose initial treatment, a de-escalation strategy according to the clinical course, and -with exceptions- a limitation of treatment to 7 to 10 days. Rotation of antibiotics should be performed, if problems with resistances exist or no specialist for infectious diseases is available on the Intensive Care Unit.

  8. Analysis of macrolide antibiotics.

    PubMed

    Kanfer, I; Skinner, M F; Walker, R B

    1998-07-01

    The following macrolide antibiotics have been covered in this review: erythromycin and its related substances, azithromycin, clarithromycin, dirithromycin, roxithromycin, flurithromycin, josamycin, rokitamycin, kitasamycin, mycinamycin, mirosamycin, oleandomycin, rosaramicin, spiramycin and tylosin. The application of various thin-layer chromatography, paper chromatography, gas chromatography, high-performance liquid chromatography and capillary zone electrophoresis procedures for their analysis are described. These techniques have been applied to the separation and quantitative analysis of the macrolides in fermentation media, purity assessment of raw materials, assay of pharmaceutical dosage forms and the measurement of clinically useful macrolide antibiotics in biological samples such as blood, plasma, serum, urine and tissues. Data relating to the chromatographic behaviour of some macrolide antibiotics as well as the various detection methods used, such as bioautography, UV spectrophotometry, fluorometry, electrochemical detection, chemiluminescence and mass spectrometry techniques are also included.

  9. Antibiotic Precautions in Athletes

    PubMed Central

    Fayock, Kristopher; Voltz, Matthew; Sandella, Bradley; Close, Jeremy; Lunser, Matthew; Okon, Joshua

    2014-01-01

    Context: Antibiotics are the mainstay of treatment for bacterial infections in patients of all ages. Athletes who maximally train are at risk for illness and various infections. Routinely used antibiotics have been linked to tendon injuries, cardiac arrhythmias, diarrhea, photosensitivity, cartilage issues, and decreased performance. Evidence Acquisition: Relevant articles published from 1989 to 2012 obtained through searching MEDLINE and OVID. Also, the Food and Drug Administration website was utilized. Study Design: Clinical review. Level of Evidence: Level 3. Results: The team physician should consider alternative medications in place of the “drug of choice” when adverse drug effects are a concern for an athlete’s health or performance. If alternative medications cannot be selected, secondary preventative measures, including sunscreen or probiotics, may be needed. Conclusion: Physicians choose medications based on a variety of factors to help ensure infection resolution while limiting potential side effects. Extra precautions are indicated when treating athletes with certain antibiotics. PMID:24982704

  10. Salinomycin, a polyether ionophoric antibiotic, inhibits adipogenesis

    SciTech Connect

    Szkudlarek-Mikho, Maria; Saunders, Rudel A.; Yap, Sook Fan; Ngeow, Yun Fong; Chin, Khew-Voon

    2012-11-30

    Highlights: Black-Right-Pointing-Pointer Salinomycin inhibits preadipocyte differentiation into adipocytes. Black-Right-Pointing-Pointer Salinomycin inhibits transcriptional regulation of adipogenesis. Black-Right-Pointing-Pointer Pharmacological effects of salinomycin suggest toxicity in cancer therapy. -- Abstract: The polyether ionophoric antibiotics including monensin, salinomycin, and narasin, are widely used in veterinary medicine and as food additives and growth promoters in animal husbandry including poultry farming. Their effects on human health, however, are not fully understood. Recent studies showed that salinomycin is a cancer stem cell inhibitor. Since poultry consumption has risen sharply in the last three decades, we asked whether the consumption of meat tainted with growth promoting antibiotics might have effects on adipose cells. We showed in this report that the ionophoric antibiotics inhibit the differentiation of preadipocytes into adipocytes. The block of differentiation is not due to the induction of apoptosis nor the inhibition of cell proliferation. In addition, salinomycin also suppresses the transcriptional activity of the CCAAT/enhancer binding proteins and the peroxisome proliferator-activated receptor {gamma}. These results suggest that the ionophoric antibiotics can be exploited as novel anti-obesity therapeutics and as pharmacological probes for the study of adipose biology. Further, the pharmacological effects of salinomycin could be a harbinger of its toxicity on the adipose tissue and other susceptible target cells in cancer therapy.

  11. Antibiotic prophylaxis in otolaryngologic surgery

    PubMed Central

    Ottoline, Ana Carolina Xavier; Tomita, Shiro; Marques, Marise da Penha Costa; Felix, Felippe; Ferraiolo, Priscila Novaes; Laurindo, Roberta Silveira Santos

    2013-01-01

    Summary Aim: Antibiotic prophylaxis aims to prevent infection of surgical sites before contamination or infection occurs. Prolonged antibiotic prophylaxis does not enhance the prevention of surgical infection and is associated with higher rates of antibiotic-resistant microorganisms. This review of the literature concerning antibiotic prophylaxis, with an emphasis on otolaryngologic surgery, aims to develop a guide for the use of antibiotic prophylaxis in otolaryngologic surgery in order to reduce the numbers of complications stemming from the indiscriminate use of antibiotics. PMID:25991999

  12. Tackling antibiotic resistance.

    PubMed

    Bush, Karen; Courvalin, Patrice; Dantas, Gautam; Davies, Julian; Eisenstein, Barry; Huovinen, Pentti; Jacoby, George A; Kishony, Roy; Kreiswirth, Barry N; Kutter, Elizabeth; Lerner, Stephen A; Levy, Stuart; Lewis, Kim; Lomovskaya, Olga; Miller, Jeffrey H; Mobashery, Shahriar; Piddock, Laura J V; Projan, Steven; Thomas, Christopher M; Tomasz, Alexander; Tulkens, Paul M; Walsh, Timothy R; Watson, James D; Witkowski, Jan; Witte, Wolfgang; Wright, Gerry; Yeh, Pamela; Zgurskaya, Helen I

    2011-11-02

    The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.

  13. Tackling antibiotic resistance

    PubMed Central

    Bush, Karen; Courvalin, Patrice; Dantas, Gautam; Davies, Julian; Eisenstein, Barry; Huovinen, Pentti; Jacoby, George A.; Kishony, Roy; Kreiswirth, Barry N.; Kutter, Elizabeth; Lerner, Stephen A.; Levy, Stuart; Lewis, Kim; Lomovskaya, Olga; Miller, Jeffrey H.; Mobashery, Shahriar; Piddock, Laura J. V.; Projan, Steven; Thomas, Christopher M.; Tomasz, Alexander; Tulkens, Paul M.; Walsh, Timothy R.; Watson, James D.; Witkowski, Jan; Witte, Wolfgang; Wright, Gerry; Yeh, Pamela; Zgurskaya, Helen I.

    2014-01-01

    The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable, but can nevertheless be controlled and must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of thirty scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, May 16-18, 2011. From these discussions emerged a priority list of steps that need to be taken to resolve this global crisis. PMID:22048738

  14. Antibiotic drug discovery.

    PubMed

    Wohlleben, Wolfgang; Mast, Yvonne; Stegmann, Evi; Ziemert, Nadine

    2016-09-01

    Due to the threat posed by the increase of highly resistant pathogenic bacteria, there is an urgent need for new antibiotics; all the more so since in the last 20 years, the approval for new antibacterial agents had decreased. The field of natural product discovery has undergone a tremendous development over the past few years. This has been the consequence of several new and revolutionizing drug discovery and development techniques, which is initiating a 'New Age of Antibiotic Discovery'. In this review, we concentrate on the most significant discovery approaches during the last and present years and comment on the challenges facing the community in the coming years. PMID:27470984

  15. Antibiotics in Animal Products

    NASA Astrophysics Data System (ADS)

    Falcão, Amílcar C.

    The administration of antibiotics to animals to prevent or treat diseases led us to be concerned about the impact of these antibiotics on human health. In fact, animal products could be a potential vehicle to transfer drugs to humans. Using appropri ated mathematical and statistical models, one can predict the kinetic profile of drugs and their metabolites and, consequently, develop preventive procedures regarding drug transmission (i.e., determination of appropriate withdrawal periods). Nevertheless, in the present chapter the mathematical and statistical concepts for data interpretation are strictly given to allow understanding of some basic pharma-cokinetic principles and to illustrate the determination of withdrawal periods

  16. Antibiotics and antibiotic resistance in agroecosystems: State of the science

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review article proposes a simple causal model depicting relationships involved in dissemination of antibiotics and antibiotic resistance in agroecosystems and potential effects on human health, functioning of natural ecosystems, and agricultural productivity. Available evidence for each causal ...

  17. Effects of antibiotic dry-cow therapy and internal teat sealant on milk somatic cell counts and clinical and subclinical mastitis in early lactation.

    PubMed

    Golder, H M; Hodge, A; Lean, I J

    2016-09-01

    The objective of this study was to determine the efficacy of an internal teat sealant (TS; Teatseal; Zoetis Australia, Silverwater, NSW, Australia), when used in combination with antibiotic dry-cow therapy (ADCT) administered at dry-off, on milk individual somatic cell count (ISCC), milk production and components, and the incidence of clinical and subclinical mastitis in dairy cows up to 60 d after calving, when compared with ADCT only. Multiparous Holstein, Jersey, or Holstein cross cows (n=2,200) from 8 farms in southern and eastern Australia were randomly assigned to treatment of all 4 quarters with ADCT alone or with ADCT plus TS (ADCT + TS) at dry-off in this randomized, multisite clinical trial. Individual milk yield, fat and protein percentages, and ISCC were measured at intervals of 14±3 d after calving for the first 60 d of lactation. The first measurement occurred between 10 and 24 d after calving. Clinical mastitis and health events were recorded from dry-off to 60 d of lactation. Milk samples were collected from first cases of clinical mastitis and subjected to bacteriology. Treatment and the interaction of treatment by time did not affect milk yield, ISCC weighted by milk yield, or fat and protein percentages. Treatment with ADCT + TS decreased geometric mean ISCC compared with treatment with ADCT alone over the first 60 d of lactation. Geometric mean ISCC (×10(3) cells/mL) was 32.0 [95% confidence interval (CI): 26.8 to 38.3] and 43.5 (95% CI: 36.2 to 52.1) for ADCT + TS and ADCT alone, respectively. The odds of at least 1 case of subclinical mastitis (ISCC ≥250,000 cells/mL) were 1.9 times higher (95% CI: 1.4 to 2.6) with ADCT alone in the first 60 d of lactation compared with ADCT + TS. Use of ADCT + TS reduced the estimated incidence of at least 1 case of subclinical mastitis on all 8 farms, compared with use of ADCT alone. Only 4 cows that calved 40 to 100 d after dry-off had a first case of clinical mastitis in the dry period. Five percent of

  18. Effects of antibiotic dry-cow therapy and internal teat sealant on milk somatic cell counts and clinical and subclinical mastitis in early lactation.

    PubMed

    Golder, H M; Hodge, A; Lean, I J

    2016-09-01

    The objective of this study was to determine the efficacy of an internal teat sealant (TS; Teatseal; Zoetis Australia, Silverwater, NSW, Australia), when used in combination with antibiotic dry-cow therapy (ADCT) administered at dry-off, on milk individual somatic cell count (ISCC), milk production and components, and the incidence of clinical and subclinical mastitis in dairy cows up to 60 d after calving, when compared with ADCT only. Multiparous Holstein, Jersey, or Holstein cross cows (n=2,200) from 8 farms in southern and eastern Australia were randomly assigned to treatment of all 4 quarters with ADCT alone or with ADCT plus TS (ADCT + TS) at dry-off in this randomized, multisite clinical trial. Individual milk yield, fat and protein percentages, and ISCC were measured at intervals of 14±3 d after calving for the first 60 d of lactation. The first measurement occurred between 10 and 24 d after calving. Clinical mastitis and health events were recorded from dry-off to 60 d of lactation. Milk samples were collected from first cases of clinical mastitis and subjected to bacteriology. Treatment and the interaction of treatment by time did not affect milk yield, ISCC weighted by milk yield, or fat and protein percentages. Treatment with ADCT + TS decreased geometric mean ISCC compared with treatment with ADCT alone over the first 60 d of lactation. Geometric mean ISCC (×10(3) cells/mL) was 32.0 [95% confidence interval (CI): 26.8 to 38.3] and 43.5 (95% CI: 36.2 to 52.1) for ADCT + TS and ADCT alone, respectively. The odds of at least 1 case of subclinical mastitis (ISCC ≥250,000 cells/mL) were 1.9 times higher (95% CI: 1.4 to 2.6) with ADCT alone in the first 60 d of lactation compared with ADCT + TS. Use of ADCT + TS reduced the estimated incidence of at least 1 case of subclinical mastitis on all 8 farms, compared with use of ADCT alone. Only 4 cows that calved 40 to 100 d after dry-off had a first case of clinical mastitis in the dry period. Five percent of

  19. Evaluation of the sensitizing potential of antibiotics in vitro using the human cell lines THP-1 and MUTZ-LC and primary monocyte-derived dendritic cells.

    PubMed

    Sebastian, Katrin; Ott, Hagen; Zwadlo-Klarwasser, Gabriele; Skazik-Voogt, Claudia; Marquardt, Yvonne; Czaja, Katharina; Merk, Hans F; Baron, Jens Malte

    2012-08-01

    Since the 7th amendment to the EU cosmetics directive foresees a complete ban on animal testing, alternative in vitro methods have been established to evaluate the sensitizing potential of small molecular weight compounds. To find out whether these novel in vitro assays are also capable to predict the sensitizing potential of small molecular weight drugs, model compounds such as beta-lactams and sulfonamides - which are the most frequent cause of adverse drug reactions - were co-incubated with THP-1, MUTZ-LC, or primary monocyte-derived dendritic cells for 48 h and subsequent expression of selected marker genes (IL-8, IL-1β, CES1, NQO1, GCLM, PIR and TRIM16) was studied by real time PCR. Benzylpenicillin and phenoxymethylpenicillin were recognized as sensitizing compounds because they are capable to induce the mRNA expression of these genes in moDCs and, except for IL-8, in THP-1 cells but not in MUTZ-LC. Ampicillin stimulated the expression of some marker genes in moDCs and THP-1 cells. SMX did not affect the expression of these genes in THP-1, however, in moDCs, at least PIR was enhanced and there was an increase of the release of IL-8. These data reveal that novel in vitro DC based assays might play a role in the evaluation of the allergenic potential of novel drug compounds, but these systems seem to lack the ability to detect the sensitizing potential of prohaptens that require metabolic activation prior to sensitization and moDCs seem to be superior with regard to the sensitivity compared with THP-1 and MUTZ-3 cell lines. PMID:22609641

  20. Suppression of antibiotic resistance acquisition by combined use of antibiotics.

    PubMed

    Suzuki, Shingo; Horinouchi, Takaaki; Furusawa, Chikara

    2015-10-01

    We analyzed the effect of combinatorial use of antibiotics with a trade-off relationship of resistance, i.e., resistance acquisition to one drug causes susceptibility to the other drug, and vice versa, on the evolution of antibiotic resistance. We demonstrated that this combinatorial use of antibiotics significantly suppressed the acquisition of resistance.

  1. Mechanisms of Antibiotic Resistance

    PubMed Central

    Munita, Jose M.; Arias, Cesar A.

    2015-01-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have emerged not only in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice providing specific examples in relevant bacterial pathogens. PMID:27227291

  2. [Antibiotical prophylaxy in gynecology].

    PubMed

    Záhumenský, J; Menzlová, E; Zmrhal, J; Kučera, E

    2013-08-01

    Gynecological surgery is considered to be clear with possible contamination by gram-positive cocci from the skin, gram-negatives from the perineum or groins or polymicrobial biocenosis from vagina, depending on the surgical approach. Antibiotical prophylaxy enforces the natural mechanisms of immunity and helps to exclude present infection. There were presented many studies comparing useful effect of prophylaxis in gynecological surgery. The benefits of antibiotical prophylaxy before IUD insertion, before the cervical surgery and before hysteroscopies were not verified. On the other hand the prophylaxy of vaginal surgery including vaginal hysterectomy decreases the number of postoperative febrile complications. The positive influence of prophylaxis before the simple laparoscopy and laparoscopy without bowel injury or the opening of the vagina was not evidently verified. In abdominal hysterectomy the antibiotical prophylaxy decreases the incidence of postoperative complications significantly. The administration of 2 g of cefazolin can be recommended. In procedures taking more than 3 hours the repeated administration of cefazolin is suitable. New urogynecological procedures, using mesh implants, were not sufficiently evaluated as for postoperative infections and the posible antibiotical effect. The presence of implant in possibly non sterile area should be considered as high risc of postoperative complications. PMID:24040985

  3. Mechanisms of Antibiotic Resistance.

    PubMed

    Munita, Jose M; Arias, Cesar A

    2016-04-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic "attack" is the prime example of bacterial adaptation and the pinnacle of evolution. "Survival of the fittest" is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens. PMID:27227291

  4. Resistance-Resistant Antibiotics

    PubMed Central

    Oldfield, Eric; Feng, Xinxin

    2014-01-01

    New antibiotics are needed because as drug resistance is increasing, the introduction of new antibiotics is decreasing. Here, we discuss six possible approaches to develop ‘resistance-resistant’ antibiotics. First, multi-target inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy due to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, re-purposing existing drugs can lead to combinations of multi-target therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and in some cases suggest that sensitivity to existing antibiotics may be restored, in otherwise drug resistant organisms. PMID:25458541

  5. Antibiotics before surgery.

    PubMed

    Kaatz, B

    1996-01-01

    The antimicrobial era (along with greater surgical skill and precision) has brought us relative safety for procedures that previously were fraught with danger. Civil War amputation surgeries, for example, had an extraordinarily high incidence of infections and mortality. Staying aware of and avoiding the small, but real, risks associated with surgical antibiotic prophylaxis will help sustain the advances we enjoy today. PMID:8650524

  6. Antibiotic prophylaxis in primary immune deficiency disorders.

    PubMed

    Kuruvilla, Merin; de la Morena, Maria Teresa

    2013-01-01

    Long-term prophylactic antibiotics are being widely implemented as primary or adjunctive therapy in primary immune deficiencies. This practice has transformed clinical outcomes in the setting of chronic granulomatous disease, complement deficiencies, Mendelian susceptibility to mycobacterial disease, Wiskott-Aldrich syndrome, hyper-IgE syndrome, Toll signaling defects, and prevented Pneumocystis in patients with T-cell deficiencies. Yet, controlled trials are few in the context of primary antibody deficiency syndromes, and most of this practice has been extrapolated from data in patients who are immune competent and with recurrent acute otitis media, chronic rhinosinusitis, cystic fibrosis, and bronchiectasis. The paucity of guidelines on the subject is reflected in recent surveys among practicing immunologists that highlight differences of habit regarding this treatment. Such discrepancies reinforce the lack of standard protocols on the subject. This review will provide evidence for the use of antibiotic prophylaxis in various primary immune deficiency populations, especially highlighting the role antibiotic prophylaxis in primary antibody deficiency syndromes. We also discussed the relationship of long-term antibiotic use and the prevalence of resistant pathogens. Overall, examination of available data on the use of prophylactic antibiotics in antibody deficiency syndromes merit future investigation in well-designed multicenter prospective trials because this population has few other management options.

  7. Antibiotics, pediatric dysbiosis, and disease.

    PubMed

    Vangay, Pajau; Ward, Tonya; Gerber, Jeffrey S; Knights, Dan

    2015-05-13

    Antibiotics are by far the most common medications prescribed for children. Recent epidemiological data suggests an association between early antibiotic use and disease phenotypes in adulthood. Antibiotic use during infancy induces imbalances in gut microbiota, called dysbiosis. The gut microbiome's responses to antibiotics and its potential link to disease development are especially complex to study in the changing infant gut. Here, we synthesize current knowledge linking antibiotics, dysbiosis, and disease and propose a framework for studying antibiotic-related dysbiosis in children. We recommend future studies into the microbiome-mediated effects of antibiotics focused on four types of dysbiosis: loss of keystone taxa, loss of diversity, shifts in metabolic capacity, and blooms of pathogens. Establishment of a large and diverse baseline cohort to define healthy infant microbiome development is essential to advancing diagnosis, interpretation, and eventual treatment of pediatric dysbiosis. This approach will also help provide evidence-based recommendations for antibiotic usage in infancy.

  8. Investigating the Antibiotic Resistance Problem.

    ERIC Educational Resources Information Center

    Lawson, Michael; Lawson, Amy L.

    1998-01-01

    Seeks to give teachers useful information on the extent of the problem of antibiotic-resistant bacteria, mechanisms bacteria use to resist antibiotics, the causes of the emergence of antibiotic-resistant organisms, and practices that can prevent or reverse this trend. Contains 19 references. (DDR)

  9. What Can Be Done about Antibiotic Resistance?

    MedlinePlus

    ... antibiotics for treating human disease. (See Antibiotics in agriculture .) Is there any international action on the antibiotic ... and reducing antibiotic use in animal farming and agriculture. Experts agree that a global system for tracking ...

  10. Antibiotic induced bacterial lysis provides a reservoir of persisters.

    PubMed

    Podlesek, Zdravko; Butala, Matej; Šakanović, Aleksandra; Žgur-Bertok, Darja

    2016-04-01

    In a genetically uniform bacterial population a small subset of antibiotic-susceptible cells enter an antibiotic tolerant state and are hence referred to as persisters. These have been proposed to be rare phenotypic variants with several stochastically activated independent parallel processes. Here we show an overlooked phenomenon, bacterial tolerance of extraordinary high levels of ampicillin due to encasement of viable cells by an antibiotic induced network of cell debris. This matrix shields the entrapped cells from contact with the bacteriolytic β-lactam antibiotic ampicillin and may be an underlying cause of notable variations in the level of ampicillin tolerant persisters as well as of considerable medical significance. Disruption of the matrix leads to the rapid elimination of hidden survivors, revealing their metabolically active state. PMID:26821377

  11. Stigmatellin, a new antibiotic from Stigmatella aurantiaca (Myxobacterales). I. Production, physico-chemical and biological properties.

    PubMed

    Kunze, B; Kemmer, T; Höfle, G; Reichenbach, H

    1984-05-01

    An antibiotic activity was extracted from the cell mass of the myxobacterium, Stigmatella aurantiaca strain Sg a15. The antibiotic was toxic for yeasts and filamentous fungi, but not for most bacteria. The compound had the molecular formula C30H42O7, appears to be a new antibiotic, and was named stigmatellin. In addition to stigmatellin, the strain produced relatively large quantities of a second, structurally unrelated antibiotic, a mixture of three myxalamid homologues. PMID:6429114

  12. A simple classification method for residual antibiotics using E. coli cells transformed by the calcium chloride method and drug resistance plasmid DNA.

    PubMed

    Lin, S Y; Kondo, F

    2001-01-01

    Using three different plasmid DNA codings for kanamycin (KM), chloramphenicol (CP), and ampicillin- (AMP) and tetracycline- (TC) resistance, four different competent Escherichia coli strains were transformed by the calcium chloride method to produce KM-, CP- and AMP- and TC-resistant strains. Evaluation of minimum inhibitory concentrations (MIC) of 22 antibiotics, showed KM-resistant E. coli to be cross resistant only to fradiomycin (FRM); CP-resistant E. coli, especially HB101 and JM109 strains, exhibited cross-resistance only to thiamphenicol (TP). On the other hand, AMP- and TC-resistant E. coli showed cross resistance to several penicillins, tetracyclines and erythromycin. E. coli ATCC-27166, the strain most sensitive to all drugs in this experiment, was employed for disc diffusion experiments and from the pattern of appearance of the inhibition zone, eight major antibiotics were divided into three groups depending on their activity against containing each of the three plasmids. Only gentamicin (GM) activity was not affected by any of the drug resistant strains. Assay techniques utilizing three resistant strains may be the technique for screening foods for antibiotic residues in the future.

  13. Minocycline: far beyond an antibiotic

    PubMed Central

    Garrido-Mesa, N; Zarzuelo, A; Gálvez, J

    2013-01-01

    Minocycline is a second-generation, semi-synthetic tetracycline that has been in therapeutic use for over 30 years because of its antibiotic properties against both gram-positive and gram-negative bacteria. It is mainly used in the treatment of acne vulgaris and some sexually transmitted diseases. Recently, it has been reported that tetracyclines can exert a variety of biological actions that are independent of their anti-microbial activity, including anti-inflammatory and anti-apoptotic activities, and inhibition of proteolysis, angiogenesis and tumour metastasis. These findings specifically concern to minocycline as it has recently been found to have multiple non-antibiotic biological effects that are beneficial in experimental models of various diseases with an inflammatory basis, including dermatitis, periodontitis, atherosclerosis and autoimmune disorders such as rheumatoid arthritis and inflammatory bowel disease. Of note, minocycline has also emerged as the most effective tetracycline derivative at providing neuroprotection. This effect has been confirmed in experimental models of ischaemia, traumatic brain injury and neuropathic pain, and of several neurodegenerative conditions including Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis and spinal cord injury. Moreover, other pre-clinical studies have shown its ability to inhibit malignant cell growth and activation and replication of human immunodeficiency virus, and to prevent bone resorption. Considering the above-mentioned findings, this review will cover the most important topics in the pharmacology of minocycline to date, supporting its evaluation as a new therapeutic approach for many of the diseases described herein. PMID:23441623

  14. Bacterial cheating limits the evolution of antibiotic resistance

    NASA Astrophysics Data System (ADS)

    Chao, Hui Xiao; Datta, Manoshi; Yurtsev, Eugene; Gore, Jeff

    2011-03-01

    The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain--which does not contribute to breaking down the antibiotic--may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we experimentally find that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors found in nature.

  15. Rapid determination of antibiotic resistance in E. coli using dielectrophoresis

    NASA Astrophysics Data System (ADS)

    Hoettges, Kai F.; Dale, Jeremy W.; Hughes, Michael P.

    2007-09-01

    In recent years, infections due to antibiotic-resistant strains of bacteria such as methillicin-resistant Staphylococcus aureus and ciprofloxacin-resistant Escherichia coli are on the rise, and with them the demand for rapid antibiotic testing is also rising. Conventional tests, such as disc diffusion testing, require a primary sample to be tested in the presence of a number of antibiotics to verify which antibiotics suppress growth, which take approximately 24 h to complete and potentially place the patient at severe risk. In this paper we describe the use of dielectrophoresis as a rapid marker of cell death, by detecting changes in the electrophysiology of the cell caused by the administration of an antibiotic. In contrast to other markers, the electrophysiology of the cell changes rapidly during cell death allowing live cells to be distinguished from dead (or dying) cells without the need for culturing. Using polymyxin B as an example antibiotic, our studies indicate that significant changes in cell characteristics can be observed as soon as 1 h passes after isolating a culture from nutrient broth.

  16. Antibiotic alternatives: the substitution of antibiotics in animal husbandry?

    PubMed

    Cheng, Guyue; Hao, Haihong; Xie, Shuyu; Wang, Xu; Dai, Menghong; Huang, Lingli; Yuan, Zonghui

    2014-01-01

    It is a common practice for decades to use of sub-therapeutic dose of antibiotics in food-animal feeds to prevent animals from diseases and to improve production performance in modern animal husbandry. In the meantime, concerns over the increasing emergence of antibiotic-resistant bacteria due to the unreasonable use of antibiotics and an appearance of less novelty antibiotics have prompted efforts to develop so-called alternatives to antibiotics. Whether or not the alternatives could really replace antibiotics remains a controversial issue. This review summarizes recent development and perspectives of alternatives to antibiotics. The mechanism of actions, applications, and prospectives of the alternatives such as immunity modulating agents, bacteriophages and their lysins, antimicrobial peptides, pro-, pre-, and synbiotics, plant extracts, inhibitors targeting pathogenicity (bacterial quorum sensing, biofilm, and virulence), and feeding enzymes are thoroughly discussed. Lastly, the feasibility of alternatives to antibiotics is deeply analyzed. It is hard to conclude that the alternatives might substitute antibiotics in veterinary medicine in the foreseeable future. At the present time, prudent use of antibiotics and the establishment of scientific monitoring systems are the best and fastest way to limit the adverse effects of the abuse of antibiotics and to ensure the safety of animal-derived food and environment.

  17. Antibiotic alternatives: the substitution of antibiotics in animal husbandry?

    PubMed Central

    Cheng, Guyue; Hao, Haihong; Xie, Shuyu; Wang, Xu; Dai, Menghong; Huang, Lingli; Yuan, Zonghui

    2014-01-01

    It is a common practice for decades to use of sub-therapeutic dose of antibiotics in food-animal feeds to prevent animals from diseases and to improve production performance in modern animal husbandry. In the meantime, concerns over the increasing emergence of antibiotic-resistant bacteria due to the unreasonable use of antibiotics and an appearance of less novelty antibiotics have prompted efforts to develop so-called alternatives to antibiotics. Whether or not the alternatives could really replace antibiotics remains a controversial issue. This review summarizes recent development and perspectives of alternatives to antibiotics. The mechanism of actions, applications, and prospectives of the alternatives such as immunity modulating agents, bacteriophages and their lysins, antimicrobial peptides, pro-, pre-, and synbiotics, plant extracts, inhibitors targeting pathogenicity (bacterial quorum sensing, biofilm, and virulence), and feeding enzymes are thoroughly discussed. Lastly, the feasibility of alternatives to antibiotics is deeply analyzed. It is hard to conclude that the alternatives might substitute antibiotics in veterinary medicine in the foreseeable future. At the present time, prudent use of antibiotics and the establishment of scientific monitoring systems are the best and fastest way to limit the adverse effects of the abuse of antibiotics and to ensure the safety of animal-derived food and environment. PMID:24860564

  18. [Prophylactic antibiotics in plastic surgery].

    PubMed

    Sabovcík, R; Kyslan, K

    2006-06-01

    There is no consensus on the use of prophylactic antibiotics in plastic surgery to prevent postoperative infection. This study was performed to investigate whether the use of prophylactic antibiotics has an effect on postoperative infection rate. A total of 500 patients were classified into 3 groups based on their diagnosis. Approximately half of the cases received amoxicilin/clavulanate combination the other half had no antibiotics. Wound infection was observed in the post operative period. According to our clinical findings, antibiotic prophylaxis is not necessary in plastic surgery in all patients. We did not find significant difference between the antibiotic prophylaxis and placebo group.

  19. Naphthyridinomycin, a DNA-reactive antibiotic.

    PubMed Central

    Zmijewski, M J; Miller-Hatch, K; Goebel, M

    1982-01-01

    Naphthyridinomycin is a novel quinone antibiotic that is produced in liquid shake cultures by Streptomyces lusitanus. Fermentation studies have shown that this antibiotic is produced maximally after 96 h of cell growth. L-[methyl-3H]methionine efficiently labels naphthyridinomycin when it is added to a fermentation mixture 24 h before culture is harvested. Unlabeled and radioactively labeled naphthyridinomycin were used to determine the mechanism of action of this unique antibiotic. Naphthyridinomycin inhibited bacterial growth primarily by inhibiting DNA synthesis. The structural similarity between naphthyridinomycin and the saframycins suggested that naphthyridinomycin might inhibit DNA synthesis by binding to the template. In vitro studies with radiolabeled naphthyridinomycin indicated that this antibiotic does specifically bind to calf thymus DNA. The binding reaction was enhanced by adding sulfhydryl-containing compounds; dithiothreitol was the best activating agent. DNA-naphthyridinomycin complexes were a poor substrate for enzymes that catalyze DNA-directed DNA and RNA syntheses. These results showed that naphthyridinomycin is similar to the saframycins in its reactivity toward DNA and suggested that the mechanism by which naphthyridinomycin inhibits DNA synthesis is through its ability to bind specifically to the DNA template of the cell. PMID:7103457

  20. New approach for specific determination of antibiotics by use of luminescent Escherichia coli and immune serum.

    PubMed

    Vlasova, Irina I; Asrieli, Tatyana V; Gavrilova, Elisaveta M; Danilov, Vadim S

    2004-02-01

    This paper describes a possible application of luminescent Escherichia coli activated by blood serum for high-sensitivity and high-specificity assays of antibiotics in solutions. Antibiotics inhibited luminescence of a genetically engineered E. coli strain; the system sensitivity to some antibiotics grew notably after the cells had been preactivated by blood serum. The highest level of sensitivity (2.8 +/- 0.6 ng/ml) of luminescent cells was obtained for aminoglycoside antibiotics (gentamicin and streptomycin). It is feasible to create the specific biosensor for antibiotics on the basis of bioluminescent E. coli strains by applying sera containing antibodies against the antibiotic under assay. The presence of antibodies specific for gentamicin in serum affects inhibition of luminescent cells by gentamicin but not inhibition by other antibiotics.

  1. Reviving old antibiotics.

    PubMed

    Theuretzbacher, Ursula; Van Bambeke, Françoise; Cantón, Rafael; Giske, Christian G; Mouton, Johan W; Nation, Roger L; Paul, Mical; Turnidge, John D; Kahlmeter, Gunnar

    2015-08-01

    In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to 're-develop' these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today's standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections.

  2. When antibiotics are unnecessary.

    PubMed

    Hirschmann, J V

    2009-01-01

    Dermatologists can decrease unnecessary use of antimicrobial agents by avoiding them in situations wherein good evidence indicates that they are ineffective. Controlled trials indicate that antimicrobial agents are unhelpful in treating cutaneous abscesses, inflamed epidermal cysts, uninfected atopic eczema, and cutaneous ulcers caused by venous insufficiency or diabetes in the absence of significant contiguous soft-tissue inflammation. Prophylactic antibiotics are rarely appropriate for routine dermatologic surgery and are not indicated for patients who have prosthetic joints or vascular grafts. They are recommended only for a small group of patients who have abnormal cardiac valves, and then only with surgery involving clearly infected skin or soft-tissue. Topical antibiotics are no better than white petrolatum in covering sutured wounds, and with moist occlusive dressings, no ointment is necessary. PMID:18984370

  3. The Comprehensive Antibiotic Resistance Database

    PubMed Central

    McArthur, Andrew G.; Waglechner, Nicholas; Nizam, Fazmin; Yan, Austin; Azad, Marisa A.; Baylay, Alison J.; Bhullar, Kirandeep; Canova, Marc J.; De Pascale, Gianfranco; Ejim, Linda; Kalan, Lindsay; King, Andrew M.; Koteva, Kalinka; Morar, Mariya; Mulvey, Michael R.; O'Brien, Jonathan S.; Pawlowski, Andrew C.; Piddock, Laura J. V.; Spanogiannopoulos, Peter; Sutherland, Arlene D.; Tang, Irene; Taylor, Patricia L.; Thaker, Maulik; Wang, Wenliang; Yan, Marie; Yu, Tennison

    2013-01-01

    The field of antibiotic drug discovery and the monitoring of new antibiotic resistance elements have yet to fully exploit the power of the genome revolution. Despite the fact that the first genomes sequenced of free living organisms were those of bacteria, there have been few specialized bioinformatic tools developed to mine the growing amount of genomic data associated with pathogens. In particular, there are few tools to study the genetics and genomics of antibiotic resistance and how it impacts bacterial populations, ecology, and the clinic. We have initiated development of such tools in the form of the Comprehensive Antibiotic Research Database (CARD; http://arpcard.mcmaster.ca). The CARD integrates disparate molecular and sequence data, provides a unique organizing principle in the form of the Antibiotic Resistance Ontology (ARO), and can quickly identify putative antibiotic resistance genes in new unannotated genome sequences. This unique platform provides an informatic tool that bridges antibiotic resistance concerns in health care, agriculture, and the environment. PMID:23650175

  4. Pneumococcal resistance to antibiotics.

    PubMed Central

    Klugman, K P

    1990-01-01

    The geographic distribution of pneumococci resistant to one or more of the antibiotics penicillin, erythromycin, trimethoprim-sulfamethoxazole, and tetracycline appears to be expanding, and there exist foci of resistance to chloramphenicol and rifampin. Multiply resistant pneumococci are being encountered more commonly and are more often community acquired. Factors associated with infection caused by resistant pneumococci include young age, duration of hospitalization, infection with a pneumococcus of serogroup 6, 19, or 23 or serotype 14, and exposure to antibiotics to which the strain is resistant. At present, the most useful drugs for the management of resistant pneumococcal infections are cefotaxime, ceftriaxone, vancomycin, and rifampin. If the strains are susceptible, chloramphenicol may be useful as an alternative, less expensive agent. Appropriate interventions for the control of resistant pneumococcal outbreaks include investigation of the prevalence of resistant strains, isolation of patients, possible treatment of carriers, and reduction of usage of antibiotics to which the strain is resistant. The molecular mechanisms of penicillin resistance are related to the structure and function of penicillin-binding proteins, and the mechanisms of resistance to other agents involved in multiple resistance are being elucidated. Recognition is increasing of the standard screening procedure for penicillin resistance, using a 1-microgram oxacillin disk. PMID:2187594

  5. Surveillance of antibiotic resistance

    PubMed Central

    Johnson, Alan P.

    2015-01-01

    Surveillance involves the collection and analysis of data for the detection and monitoring of threats to public health. Surveillance should also inform as to the epidemiology of the threat and its burden in the population. A further key component of surveillance is the timely feedback of data to stakeholders with a view to generating action aimed at reducing or preventing the public health threat being monitored. Surveillance of antibiotic resistance involves the collection of antibiotic susceptibility test results undertaken by microbiology laboratories on bacteria isolated from clinical samples sent for investigation. Correlation of these data with demographic and clinical data for the patient populations from whom the pathogens were isolated gives insight into the underlying epidemiology and facilitates the formulation of rational interventions aimed at reducing the burden of resistance. This article describes a range of surveillance activities that have been undertaken in the UK over a number of years, together with current interventions being implemented. These activities are not only of national importance but form part of the international response to the global threat posed by antibiotic resistance. PMID:25918439

  6. Novel antibody-antibiotic conjugate eliminates intracellular S. aureus.

    PubMed

    Lehar, Sophie M; Pillow, Thomas; Xu, Min; Staben, Leanna; Kajihara, Kimberly K; Vandlen, Richard; DePalatis, Laura; Raab, Helga; Hazenbos, Wouter L; Morisaki, J Hiroshi; Kim, Janice; Park, Summer; Darwish, Martine; Lee, Byoung-Chul; Hernandez, Hilda; Loyet, Kelly M; Lupardus, Patrick; Fong, Rina; Yan, Donghong; Chalouni, Cecile; Luis, Elizabeth; Khalfin, Yana; Plise, Emile; Cheong, Jonathan; Lyssikatos, Joseph P; Strandh, Magnus; Koefoed, Klaus; Andersen, Peter S; Flygare, John A; Wah Tan, Man; Brown, Eric J; Mariathasan, Sanjeev

    2015-11-19

    Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections. PMID:26536114

  7. A bacteria antibiotic system in space (23-F ANTIBIO)

    NASA Technical Reports Server (NTRS)

    Tixador, Rene; Gasset, G.; Eche, B.; Moatti, N.; Lapchine, L.; Woldringh, C.; Toorop, P.; Moatti, J. P.; Delmotte, F.; Tap, G.

    1995-01-01

    In order to evaluate the effects of weightlessness and cosmic radiations on the bacteria resistance to antibiotics, the Antibio 23F experiment was undertaken onboard Discovery during the 1st International Microgravity Laboratory (IML-1) mission. The effects of various antibiotic concentrations (dihydrostreptomycin) on Escherichia coli growth and cell division behavior were studied. The antibiotic binding was investigated using a radioactive tracer (tritium). The results showed that microgravity did not affect E. coli cells in regards the growth and the cell division. The antibiotic added to the culture medium induced an inhibition of the cultures both in the flight and ground controls. However, the antibiotic was less efficient in flight. The behavior of bacteria was modified, and the exponential growth rate was increased in flight. The incorporation of radioactive antibiotics in flight was comparatively different to ground incorporation, which indicated some perturbations in antibiotic binding. The experiments performed in the 1 g centrifuge did not show any difference in the cultures developed on the static rack, and could support a radiative effect of cosmic radiation to explain the results.

  8. Permeation of bacterial cells, permeation of cytoplasmic and artificial membrane vesicles, and channel formation on lipid bilayers by peptide antibiotic AS-48.

    PubMed Central

    Gálvez, A; Maqueda, M; Martínez-Bueno, M; Valdivia, E

    1991-01-01

    Peptide AS-48 induces ion permeation, which is accompanied by the collapse of the cytoplasmic membrane potential, in sensitive bacteria. Active transport by cytoplasmic membrane vesicles is also impaired by AS-48. At low concentrations, this peptide also causes permeability of liposomes to low-molecular-weight compounds without a requirement for a membrane potential. Higher antibiotic concentrations induce severe disorganization, which is visualized under electron microscopy as aggregation and formation of multilamellar structures. Electrical measurements suggest that AS-48 can form channels in lipid bilayers. Images PMID:1702784

  9. Persistence and resistance as complementary bacterial adaptations to antibiotics.

    PubMed

    Vogwill, T; Comfort, A C; Furió, V; MacLean, R C

    2016-06-01

    Bacterial persistence represents a simple of phenotypic heterogeneity, whereby a proportion of cells in an isogenic bacterial population can survive exposure to lethal stresses such as antibiotics. In contrast, genetically based antibiotic resistance allows for continued growth in the presence of antibiotics. It is unclear, however, whether resistance and persistence are complementary or alternative evolutionary adaptations to antibiotics. Here, we investigate the co-evolution of resistance and persistence across the genus Pseudomonas using comparative methods that correct for phylogenetic nonindependence. We find that strains of Pseudomonas vary extensively in both their intrinsic resistance to antibiotics (ciprofloxacin and rifampicin) and persistence following exposure to these antibiotics. Crucially, we find that persistence correlates positively to antibiotic resistance across strains. However, we find that different genes control resistance and persistence implying that they are independent traits. Specifically, we find that the number of type II toxin-antitoxin systems (TAs) in the genome of a strain is correlated to persistence, but not resistance. Our study shows that persistence and antibiotic resistance are complementary, but independent, evolutionary adaptations to stress and it highlights the key role played by TAs in the evolution of persistence.

  10. Persistence and resistance as complementary bacterial adaptations to antibiotics.

    PubMed

    Vogwill, T; Comfort, A C; Furió, V; MacLean, R C

    2016-06-01

    Bacterial persistence represents a simple of phenotypic heterogeneity, whereby a proportion of cells in an isogenic bacterial population can survive exposure to lethal stresses such as antibiotics. In contrast, genetically based antibiotic resistance allows for continued growth in the presence of antibiotics. It is unclear, however, whether resistance and persistence are complementary or alternative evolutionary adaptations to antibiotics. Here, we investigate the co-evolution of resistance and persistence across the genus Pseudomonas using comparative methods that correct for phylogenetic nonindependence. We find that strains of Pseudomonas vary extensively in both their intrinsic resistance to antibiotics (ciprofloxacin and rifampicin) and persistence following exposure to these antibiotics. Crucially, we find that persistence correlates positively to antibiotic resistance across strains. However, we find that different genes control resistance and persistence implying that they are independent traits. Specifically, we find that the number of type II toxin-antitoxin systems (TAs) in the genome of a strain is correlated to persistence, but not resistance. Our study shows that persistence and antibiotic resistance are complementary, but independent, evolutionary adaptations to stress and it highlights the key role played by TAs in the evolution of persistence. PMID:26999656

  11. The role of biofilms as environmental reservoirs of antibiotic resistance.

    PubMed

    Balcázar, José L; Subirats, Jéssica; Borrego, Carles M

    2015-01-01

    Antibiotic resistance has become a significant and growing threat to public and environmental health. To face this problem both at local and global scales, a better understanding of the sources and mechanisms that contribute to the emergence and spread of antibiotic resistance is required. Recent studies demonstrate that aquatic ecosystems are reservoirs of resistant bacteria and antibiotic resistance genes as well as potential conduits for their transmission to human pathogens. Despite the wealth of information about antibiotic pollution and its effect on the aquatic microbial resistome, the contribution of environmental biofilms to the acquisition and spread of antibiotic resistance has not been fully explored in aquatic systems. Biofilms are structured multicellular communities embedded in a self-produced extracellular matrix that acts as a barrier to antibiotic diffusion. High population densities and proximity of cells in biofilms also increases the chances for genetic exchange among bacterial species converting biofilms in hot spots of antibiotic resistance. This review focuses on the potential effect of antibiotic pollution on biofilm microbial communities, with special emphasis on ecological and evolutionary processes underlying acquired resistance to these compounds.

  12. The role of biofilms as environmental reservoirs of antibiotic resistance

    PubMed Central

    Balcázar, José L.; Subirats, Jéssica; Borrego, Carles M.

    2015-01-01

    Antibiotic resistance has become a significant and growing threat to public and environmental health. To face this problem both at local and global scales, a better understanding of the sources and mechanisms that contribute to the emergence and spread of antibiotic resistance is required. Recent studies demonstrate that aquatic ecosystems are reservoirs of resistant bacteria and antibiotic resistance genes as well as potential conduits for their transmission to human pathogens. Despite the wealth of information about antibiotic pollution and its effect on the aquatic microbial resistome, the contribution of environmental biofilms to the acquisition and spread of antibiotic resistance has not been fully explored in aquatic systems. Biofilms are structured multicellular communities embedded in a self-produced extracellular matrix that acts as a barrier to antibiotic diffusion. High population densities and proximity of cells in biofilms also increases the chances for genetic exchange among bacterial species converting biofilms in hot spots of antibiotic resistance. This review focuses on the potential effect of antibiotic pollution on biofilm microbial communities, with special emphasis on ecological and evolutionary processes underlying acquired resistance to these compounds. PMID:26583011

  13. Antibiotic resistance: an ecological imbalance.

    PubMed

    Levy, S B

    1997-01-01

    Antibiotic resistance thwarts the treatment of infectious diseases worldwide. Although a number of factors can be identified which contribute to the problem, clearly the antibiotic as a selective agent and the resistance gene as the vehicle of resistance are the two most important, making up a 'drug resistance equation'. Both are needed in order for a clinical problem to arise. Given sufficient time and quantity of antibiotic, drug resistance will eventually appear. But a public health problem is not inevitable if the two components of the drug resistance equation are kept in check. Enhancing the emergence of resistance is the case by which resistance determinants and resistant bacteria can spread locally and globally, selected by widespread use of the same antibiotics in people, animal husbandry and agriculture. Antibiotics are societal drugs. Each individual use contributes to the sum total of society's antibiotic exposure. In a broader sense, the resistance problem is ecological. In the framework of natural competition between susceptible and resistant bacteria, antibiotic use has encouraged growth of the resistant strains, leading to an imbalance in prior relationships between susceptible and resistant bacteria. To restore efficacy to earlier antibiotics and to maintain the success of new antibiotics that are introduced, we need to use antibiotics in a way which assures an ecological balance that favours the predominance of susceptible bacterial flora.

  14. Optimizing Antibiotic Use in Nursing Homes Through Antibiotic Stewardship.

    PubMed

    Sloane, Philip D; Huslage, Kirk; Kistler, Christine E; Zimmerman, Sheryl

    2016-01-01

    Antibiotic stewardship is becoming a requirement for nursing homes. Programs should be interdisciplinary and multifaceted; should have support from nursing home administrators; and should aim to promote antibiotics only when needed, not just in case. Recommended components include use of evidence-based guidelines; ongoing monitoring of antibiotic prescriptions, cultures, and study results; monitoring of health outcomes; use of nursing home-specific antibiograms; regular reporting and feedback to medical providers and nurses; and education of residents and families. PMID:27621341

  15. Rationalizing antibiotic use to limit antibiotic resistance in India+

    PubMed Central

    2011-01-01

    Antibiotic resistance, a global concern, is particularly pressing in developing nations, including India, where the burden of infectious disease is high and healthcare spending is low. The Global Antibiotic Resistance Partnership (GARP) was established to develop actionable policy recommendations specifically relevant to low- and middle-income countries where suboptimal access to antibiotics - not a major concern in high-income countries - is possibly as severe a problem as is the spread of resistant organisms. This report summarizes the situation as it is known regarding antibiotic use and growing resistance in India and recommends short and long term actions. Recommendations aim at (i) reducing the need for antibiotics; (ii) lowering resistance-enhancing drug pressure through improved antibiotic targeting, and (iii) eliminating antibiotic use for growth promotion in agriculture. The highest priority needs to be given to (i) national surveillance of antibiotic resistance and antibiotic use - better information to underpin decisions on standard treatment guidelines, education and other actions, as well as to monitor changes over time; (ii) increasing the use of diagnostic tests, which necessitates behavioural changes and improvements in microbiology laboratory capacity; (iii) setting up and/or strengthening infection control committees in hospitals; and (iv) restricting the use of antibiotics for non-therapeutic uses in agriculture. These interventions should help to reduce the spread of antibiotic resistance, improve public health directly, benefit the populace and reduce pressure on the healthcare system. Finally, increasing the types and coverage of childhood vaccines offered by the government would reduce the disease burden enormously and spare antibiotics. PMID:21985810

  16. Antibiotic and antimicrobial peptide combinations: synergistic inhibition of Pseudomonas fluorescens and antibiotic-resistant variants.

    PubMed

    Naghmouchi, Karim; Le Lay, Christophe; Baah, John; Drider, Djamel

    2012-02-01

    Variants resistant to penicillin G (RvP), streptomycin (RvS), lincomycin (RvL) and rifampicin (RvR) were developed from a colistin-sensitive isolate of Pseudomonas fluorescens LRC-R73 (P. fluorescens). Cell fatty acid composition, K(+) efflux and sensitivity to antimicrobial peptides (nisin Z, pediocin PA-1/AcH and colistin) alone or combined with antibiotics were determined. P. fluorescens was highly sensitive to kanamycin, tetracycline and chloramphenicol at minimal inhibitory concentrations of 0.366, 0.305 and 0.732 μg/ml respectively. P. fluorescens, RvP, RvS, RvL and RvR were resistant to nisin Z and pediocin PA-1/AcH at concentrations ≥100 μg/ml but sensitive to colistin at 0.076, 0.043, 0.344, 0.344 and 0.258 μg/ml respectively. A synergistic inhibitory effect (FICI ≤0.5) was observed when resistant variants were treated with peptide/antibiotic combinations. No significant effect on K(+) efflux from the resistant variants in the presence of antibiotics or peptides alone or combined was observed. The proportion of C16:0 was significantly higher in antibiotic-resistant variants than in the parent strain, accounting for 32.3%, 46.49%, 43.3%, 40.1% and 44.1% of the total fatty acids in P. fluorescens, RvP, RvS, RvL and RvR respectively. Combination of antibiotics with antimicrobial peptides could allow reduced use of antibiotics in medical applications and could help slow the emergence of bacteria resistant to antibiotics. PMID:22172555

  17. Immobilized antibiotics to prevent orthopedic implant infections

    PubMed Central

    Hickok, Noreen J.; Shapiro, Irving M.

    2012-01-01

    Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body cavity. While the majority of these implants do not become colonized by bacteria, a small percentage develops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved periprosthetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus of this review is to describe development of an implant in which an antibiotic tethered to the metal surface is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syntheses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy amines. The stable metal-antibiotic construct resists bacterial colonization and biofilm formation while remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modified implant resists challenges by bacteria that are commonly present in periprosthetic infections. While the long-term efficacy and stability is still to be established, ongoing studies support the view that this novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of orthopaedic infection. PMID:22512927

  18. Antibiotic Susceptibility Testing of the Gram-Negative Bacteria Based on Flow Cytometry.

    PubMed

    Saint-Ruf, Claude; Crussard, Steve; Franceschi, Christine; Orenga, Sylvain; Ouattara, Jasmine; Ramjeet, Mahendrasingh; Surre, Jérémy; Matic, Ivan

    2016-01-01

    Rapidly treating infections with adequate antibiotics is of major importance. This requires a fast and accurate determination of the antibiotic susceptibility of bacterial pathogens. The most frequently used methods are slow because they are based on the measurement of growth inhibition. Faster methods, such as PCR-based detection of determinants of antibiotic resistance, do not always provide relevant information on susceptibility, particularly that which is not genetically based. Consequently, new methods, such as the detection of changes in bacterial physiology caused by antibiotics using flow cytometry and fluorescent viability markers, are being explored. In this study, we assessed whether Alexa Fluor® 633 Hydrazide (AFH), which targets carbonyl groups, can be used for antibiotic susceptibility testing. Carbonylation of cellular macromolecules, which increases in antibiotic-treated cells, is a particularly appropriate to assess for this purpose because it is irreversible. We tested the susceptibility of clinical isolates of Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, to antibiotics from the three classes: β-lactams, aminoglycosides, and fluoroquinolones. In addition to AFH, we used TO-PRO®-3, which enters cells with damaged membranes and binds to DNA, and DiBAC4 (3), which enters cells with depolarized membranes. We also monitored antibiotic-induced morphological alterations of bacterial cells by analyzing light scattering signals. Although all tested dyes and light scattering signals allowed for the detection of antibiotic-sensitive cells, AFH proved to be the most suitable for the fast and reliable detection of antibiotic susceptibility.

  19. Antibiotic Susceptibility Testing of the Gram-Negative Bacteria Based on Flow Cytometry

    PubMed Central

    Saint-Ruf, Claude; Crussard, Steve; Franceschi, Christine; Orenga, Sylvain; Ouattara, Jasmine; Ramjeet, Mahendrasingh; Surre, Jérémy; Matic, Ivan

    2016-01-01

    Rapidly treating infections with adequate antibiotics is of major importance. This requires a fast and accurate determination of the antibiotic susceptibility of bacterial pathogens. The most frequently used methods are slow because they are based on the measurement of growth inhibition. Faster methods, such as PCR-based detection of determinants of antibiotic resistance, do not always provide relevant information on susceptibility, particularly that which is not genetically based. Consequently, new methods, such as the detection of changes in bacterial physiology caused by antibiotics using flow cytometry and fluorescent viability markers, are being explored. In this study, we assessed whether Alexa Fluor® 633 Hydrazide (AFH), which targets carbonyl groups, can be used for antibiotic susceptibility testing. Carbonylation of cellular macromolecules, which increases in antibiotic-treated cells, is a particularly appropriate to assess for this purpose because it is irreversible. We tested the susceptibility of clinical isolates of Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, to antibiotics from the three classes: β-lactams, aminoglycosides, and fluoroquinolones. In addition to AFH, we used TO-PRO®-3, which enters cells with damaged membranes and binds to DNA, and DiBAC4 (3), which enters cells with depolarized membranes. We also monitored antibiotic-induced morphological alterations of bacterial cells by analyzing light scattering signals. Although all tested dyes and light scattering signals allowed for the detection of antibiotic-sensitive cells, AFH proved to be the most suitable for the fast and reliable detection of antibiotic susceptibility. PMID:27507962

  20. Antibiotic Susceptibility Testing of the Gram-Negative Bacteria Based on Flow Cytometry.

    PubMed

    Saint-Ruf, Claude; Crussard, Steve; Franceschi, Christine; Orenga, Sylvain; Ouattara, Jasmine; Ramjeet, Mahendrasingh; Surre, Jérémy; Matic, Ivan

    2016-01-01

    Rapidly treating infections with adequate antibiotics is of major importance. This requires a fast and accurate determination of the antibiotic susceptibility of bacterial pathogens. The most frequently used methods are slow because they are based on the measurement of growth inhibition. Faster methods, such as PCR-based detection of determinants of antibiotic resistance, do not always provide relevant information on susceptibility, particularly that which is not genetically based. Consequently, new methods, such as the detection of changes in bacterial physiology caused by antibiotics using flow cytometry and fluorescent viability markers, are being explored. In this study, we assessed whether Alexa Fluor® 633 Hydrazide (AFH), which targets carbonyl groups, can be used for antibiotic susceptibility testing. Carbonylation of cellular macromolecules, which increases in antibiotic-treated cells, is a particularly appropriate to assess for this purpose because it is irreversible. We tested the susceptibility of clinical isolates of Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, to antibiotics from the three classes: β-lactams, aminoglycosides, and fluoroquinolones. In addition to AFH, we used TO-PRO®-3, which enters cells with damaged membranes and binds to DNA, and DiBAC4 (3), which enters cells with depolarized membranes. We also monitored antibiotic-induced morphological alterations of bacterial cells by analyzing light scattering signals. Although all tested dyes and light scattering signals allowed for the detection of antibiotic-sensitive cells, AFH proved to be the most suitable for the fast and reliable detection of antibiotic susceptibility. PMID:27507962

  1. Antibiotic resistance in pediatric urology

    PubMed Central

    Copp, Hillary L.

    2014-01-01

    Antibiotics are a mainstay in the treatment of bacterial infections, though their use is a primary risk factor for the development of antibiotic resistance. Antibiotic resistance is a growing problem in pediatric urology as demonstrated by increased uropathogen resistance. Lack of urine testing, nonselective use of prophylaxis, and poor empiric prescribing practices exacerbate this problem. This article reviews antibiotic utilization in pediatric urology with emphasis on modifiable practice patterns to potentially help mitigate the growing rates of antibiotic resistance. This includes urine testing to only treat when indicated and tailor broad-spectrum therapy as able; selective application of antibiotic prophylaxis to patients with high-grade vesicoureteral reflux and hydronephrosis with counseling regarding the importance of compliance; and using local antiobiograms, particularly pediatric-specific antiobiograms, with inpatient versus outpatient data. PMID:24688601

  2. Antibiotics from predatory bacteria

    PubMed Central

    Korp, Juliane; Vela Gurovic, María S

    2016-01-01

    Summary Bacteria, which prey on other microorganisms, are commonly found in the environment. While some of these organisms act as solitary hunters, others band together in large consortia before they attack their prey. Anecdotal reports suggest that bacteria practicing such a wolfpack strategy utilize antibiotics as predatory weapons. Consistent with this hypothesis, genome sequencing revealed that these micropredators possess impressive capacities for natural product biosynthesis. Here, we will present the results from recent chemical investigations of this bacterial group, compare the biosynthetic potential with that of non-predatory bacteria and discuss the link between predation and secondary metabolism. PMID:27340451

  3. Antibiotics from predatory bacteria.

    PubMed

    Korp, Juliane; Vela Gurovic, María S; Nett, Markus

    2016-01-01

    Bacteria, which prey on other microorganisms, are commonly found in the environment. While some of these organisms act as solitary hunters, others band together in large consortia before they attack their prey. Anecdotal reports suggest that bacteria practicing such a wolfpack strategy utilize antibiotics as predatory weapons. Consistent with this hypothesis, genome sequencing revealed that these micropredators possess impressive capacities for natural product biosynthesis. Here, we will present the results from recent chemical investigations of this bacterial group, compare the biosynthetic potential with that of non-predatory bacteria and discuss the link between predation and secondary metabolism. PMID:27340451

  4. Treating appendicitis with antibiotics.

    PubMed

    Brook, Itzhak

    2016-03-01

    A nonsurgical approach using antimicrobial agents has been advocated as the initial treatment of uncomplicated appendicitis. Several studies and meta-analyses explored this approach. Because many of these studies included individuals with resolving appendicitis, their results were biased. Antimicrobials, however, are warranted and needed for the management of surgical high-risk patients with perforated appendicitis and those with localized abscess or phlegmon. Randomized placebo-controlled trials that focus on early identification of complicated acute appendicitis patients needing surgery and that prospectively evaluate the optimal use of antibiotic treatment in patients with uncomplicated acute appendicitis are warranted.

  5. Prothracarcin, a novel antitumor antibiotic.

    PubMed

    Shimizu, K; Kawamoto, I; Tomita, F; Morimoto, M; Fujimoto, K

    1982-08-01

    A novel antibiotic, prothracarcin was isolated from the culture broth of Streptomyces umbrosus subsp. raffinophilus DO-62. The antibiotic has the molecular formula of C14H14N2O and belongs to the pyrrolo [1,4]benzodiazepine antibiotics. Its structure has been elucidated by mass and NMR spectra. It is active against Gram-positive and Gram-negative bacteria and experimental murine tumor sarcoma 180 and leukemia P388. PMID:7142014

  6. Inhibition of Peptidoglycan Synthesis by the Antibiotic Diumycin A

    PubMed Central

    Lugtenberg, E. J. J.; Hellings, J. A.; Van De Berg, G. J.

    1972-01-01

    Diumycin A, a new antibiotic, was found to inhibit cell wall synthesis by Staphylococcus aureus, a phenomenon accompanied by accumulation of uridine-5′-diphosphate-N-acetyl-muramyl-pentapeptide. The antibiotic inhibited in vitro peptidoglycan synthesis by particulate preparations of Bacillus stearothermophilus and Escherichia coli by preventing the utilization of N-acetyl-glucosamine-N-acetyl-muramyl-pentapeptide. In contrast to vancomycin, the antibiotics diumycin, prasinomycin, moenomycin, 11.837 RP, and enduracidin do not inhibit particulate d-alanine carboxypeptidase. PMID:4670441

  7. Natural and engineered biosynthesis of nucleoside antibiotics in Actinomycetes.

    PubMed

    Chen, Wenqing; Qi, Jianzhao; Wu, Pan; Wan, Dan; Liu, Jin; Feng, Xuan; Deng, Zixin

    2016-03-01

    Nucleoside antibiotics constitute an important family of microbial natural products bearing diverse bioactivities and unusual structural features. Their biosynthetic logics are unique with involvement of complex multi-enzymatic reactions leading to the intricate molecules from simple building blocks. Understanding how nature builds this family of antibiotics in post-genomic era sets the stage for rational enhancement of their production, and also paves the way for targeted persuasion of the cell factories to make artificial designer nucleoside drugs and leads via synthetic biology approaches. In this review, we discuss the recent progress and perspectives on the natural and engineered biosynthesis of nucleoside antibiotics.

  8. Reservoirs of antibiotic resistance genes.

    PubMed

    Salyers, Abigail; Shoemaker, Nadja B

    2006-01-01

    A potential concern about the use of antibiotics in animal husbundary is that, as antibiotic resistant bacteria move from the farm into the human diet, they may pass antibiotic resistance genes to bacteria that normally reside in a the human intestinal tract and from there to bacteria that cause human disease (reservoir hypothesis). In this article various approaches to evaluating the risk of agricultural use of antibiotics are assessed critically. In addition, the potential benefits of applying new technology and using new insights from the field of microbial ecology are explained.

  9. Ionomycin, a new polyether antibiotic.

    PubMed

    Liu, W C; Slusarchyk, D S; Astle, G; Trejo, W H; Brown, W E; Meyers, E

    1978-09-01

    Ionomycin, a new polyether antibiotic with a high affinity for calcium ions, is obtained in pure form from fermentation broths of Streptomyces conglobatus sp. nov. Trejo by solvent extraction. It is unique amongst known polyether antibiotics in that it has a UV absorption maximum at 300 nm. thereby distinguishing it from other antibiotics of its class. The Ca salt has the molecular formula C41H70O9Ca. Ionomycin is a narrow spectrum antibiotic being active against Gram-positive bacteria. PMID:711623

  10. Magnetic isotope effect of magnesium (25)Mg on E. coli resistance to antibiotics.

    PubMed

    Letuta, U G; Vekker, A S; Kornilova, T A; Gryaznov, A A; Cheplakov, I A

    2016-07-01

    Effects of synergism and antagonism of antibacterial drugs and magnetic isotope of magnesium (25)Mg on antibiotic resistance of bacteria E. coli were discovered. Fourteen antibiotics from seven different groups were tested. The increase in antibiotic resistance in the presence of the ion (25)Mg(2+) was discovered in E. coli cells incubated with quinolones/fluoroquinolones, indicating the inhibiting effect of the magnetic moments of nuclei (25)Mg on DNA synthesis. The change in antibiotic resistance was also detected in bacteria affected by magnesium (25)Mg and certain antibiotics from aminoglycoside and lincosamide groups. PMID:27599512

  11. Hypoionic shock treatment enables aminoglycosides antibiotics to eradicate bacterial persisters

    PubMed Central

    Jiafeng, Liu; Fu, Xinmiao; Chang, Zengyi

    2015-01-01

    Bacterial persisters, usually being considered as dormant cells that are tolerant to antibiotics, are an important source for recurrent infection and emergence of antibiotic resistant pathogens. Clinical eradication of pathogenic persisters is highly desired but greatly difficult mainly due to the substantial reduction in antibiotics uptake as well as the non-active state of the drug targets. Here we report that bacterial persisters (normal growing cells as well) can be effectively eradicated by aminoglycoside antibiotics upon hypoionic shock (e.g. pure water treatment) even for less than one minute. Such hypoionic shock potentiation effect on aminoglycosides is proton motive force-independent, and is apparently achieved by promoting the entrance of aminoglycosides, speculatively through the mechanosensitive ion channels. Our revelations may provide a simple and powerful strategy to eradicate pathogen persisters. PMID:26435063

  12. Probing minority population of antibiotic-resistant bacteria.

    PubMed

    Huang, Tianxun; Zheng, Yan; Yan, Ya; Yang, Lingling; Yao, Yihui; Zheng, Jiaxin; Wu, Lina; Wang, Xu; Chen, Yuqing; Xing, Jinchun; Yan, Xiaomei

    2016-06-15

    The evolution and spread of antibiotic-resistant pathogens has become a major threat to public health. Advanced tools are urgently needed to quickly diagnose antibiotic-resistant infections to initiate appropriate treatment. Here we report the development of a highly sensitive flow cytometric method to probe minority population of antibiotic-resistant bacteria via single cell detection. Monoclonal antibody against TEM-1 β-lactamase and Alexa Fluor 488-conjugated secondary antibody were used to selectively label resistant bacteria green, and nucleic acid dye SYTO 62 was used to stain all the bacteria red. A laboratory-built high sensitivity flow cytometer (HSFCM) was applied to simultaneously detect the side scatter and dual-color fluorescence signals of single bacteria. By using E. coli JM109/pUC19 and E. coli JM109 as the model systems for antibiotic-resistant and antibiotic-susceptible bacteria, respectively, as low as 0.1% of antibiotic-resistant bacteria were accurately quantified. By monitoring the dynamic population change of a bacterial culture with the administration of antibiotics, we confirmed that under the antimicrobial pressure, the original low population of antibiotic-resistant bacteria outcompeted susceptible strains and became the dominant population after 5hours of growth. Detection of antibiotic-resistant infection in clinical urine samples was achieved without cultivation, and the bacterial load of susceptible and resistant strains can be faithfully quantified. Overall, the HSFCM-based quantitative method provides a powerful tool for the fundamental studies of antibiotic resistance and holds the potential to provide rapid and precise guidance in clinical therapies. PMID:26852201

  13. Cryptic antifungal compounds active by synergism with polyene antibiotics.

    PubMed

    Kinoshita, Hiroshi; Yoshioka, Mariko; Ihara, Fumio; Nihira, Takuya

    2016-04-01

    The majority of antifungal compounds reported so far target the cell wall or cell membrane of fungi, suggesting that other types of antibiotics cannot exert their activity because they cannot penetrate into the cells. Therefore, if the permeability of the cell membrane could be enhanced, many antibiotics might be found to have antifungal activity. We here used the polyene antibiotic nystatin, which binds to ergosterol and forms pores at the cell membrane, to enhance the cellular permeability. In the presence of nystatin, many culture extracts from entomopathogenic fungi displayed antifungal activity. Among all the active extracts, two active components were purified and identified as helvolic acid and terramide A. Because the minimum inhibitory concentration of either compound was reduced four-fold in the presence of nystatin, it can be concluded that this screening method is useful for detecting novel antifungal activity.

  14. Electrochemically monitoring the antibiotic susceptibility of Pseudomonas aeruginosa biofilms.

    PubMed

    Webster, Thaddaeus A; Sismaet, Hunter J; Chan, I-ping J; Goluch, Edgar D

    2015-11-01

    The condition of cells in Pseudomonas aeruginosa biofilms was monitored via the electrochemical detection of the electro-active virulence factor pyocyanin in a fabricated microfluidic growth chamber coupled with a disposable three electrode cell. Cells were exposed to 4, 16, and 100 mg L(-1) colistin sulfate after overnight growth. At the end of testing, the measured maximum peak current (and therefore pyocyanin concentration) was reduced by approximately 68% and 82% in P. aeruginosa exposed to 16 and 100 mg L(-1) colistin sulfate, respectively. Samples were removed from the microfluidic chamber, analyzed for viability using staining, and streaked onto culture plates to confirm that the P. aeruginosa cells were affected by the antibiotics. The correlation between electrical signal drop and the viability of P. aeruginosa cells after antibiotic exposure highlights the usefulness of this approach for future low cost antibiotic screening applications.

  15. Core-shell supramolecular gelatin nanoparticles for adaptive and "on-demand" antibiotic delivery.

    PubMed

    Li, Li-Li; Xu, Jun-Hua; Qi, Guo-Bin; Zhao, Xingzhong; Yu, Faquan; Wang, Hao

    2014-05-27

    The treatment of bacterial infection is one of the most challenging tasks in the biomedical field. Antibiotics were developed over 70 years and are regarded as the most efficient type of drug to treat bacterial infection. However, there is a concern that the overuse of antibiotics can lead to a growing number of multidrug-resistant bacteria. The development of antibiotic delivery systems to improve the biodistribution and bioavailability of antibiotics is a practical strategy for reducing the generation of antibiotic resistance and increasing the lifespan of newly developed antibiotics. Here we present an antibiotic delivery system (Van⊂SGNPs@RBC) based on core-shell supramolecular gelatin nanoparticles (SGNPs) for adaptive and "on-demand" antibiotic delivery. The core composed of cross-linked SGNPs allows for bacterial infection-microenvironment responsive release of antibiotics. The shell coated with uniform red blood cell membranes executes the function of disguise for reducing the clearance by the immune system during the antibiotic delivery, as well as absorbs the bacterial exotoxin to relieve symptoms caused by bacterial infection. This approach demonstrates an innovative and biomimetic antibiotic delivery system for the treatment of bacterial infection with a minimum dose of antibiotics.

  16. Comparative evaluation of prophylactic single-dose intravenous antibiotic with postoperative antibiotics in elective urologic surgery

    PubMed Central

    Moslemi, Mohammad K; Movahed, Seyed M Moosavi; Heidari, Akram; Saghafi, Hossein; Abedinzadeh, Mehdi

    2010-01-01

    Background Unrestricted antibiotic use is very common in Iran. As a result, emergence of resistant organisms is commonplace. Antibiotic prophylaxis in surgery consists of a short antibiotic course given immediately before the procedure in order to prevent development of a surgical site infection. The basic principle of prophylaxis is to maintain effective concentrations of an antibiotic active against the commonest pathogens during the entire surgery. Materials and methods We prospectively investigated 427 urologic surgery cases in our department between August 2008 and September 2009 (Group1). As reference cases, we retrospectively reviewed 966 patients who underwent urologic surgery between May 2004 and May 2008 (Group 2) who were administered antibiotics without any restriction. Prophylactic antibiotics such as cefazolin were administered intravenously according to our protocol. Postoperative body temperature, peripheral white blood cell counts, urinalysis, and urine culture were checked. Results To judge perioperative infections, wound condition and general condition were evaluated in terms of surgical site infection, as well as remote infection and urinary tract infection, up to postoperative day 30. Surgical site infection was defined as the presence of swelling, tenderness, redness, or drainage of pus from the wound, superficially or deeply. Remote infection was defined as occurrence of pneumonia, sepsis, or urinary tract infection. Perioperative infection rates (for surgical site and remote infection) in Group 1 and Group 2 were nine of 427 (2.6%) and 24 of 966 (2.5%), respectively. Surgical site infection rates of categories A and B in Group 1 were 0 and two (0.86%), respectively, while those in Group 2 were 0 and five (0.92%), respectively. There was no significant difference in infection rates in terms of remote infection and surgical site infection between Group 1 and Group 2 (P = 0.670). The amounts, as well as the prices, for intravenously

  17. Uptake of antibiotics by human polymorphonuclear leukocyte cytoplasts

    SciTech Connect

    Hand, W.L.; King-Thompson, N.L. , Decatur, GA )

    1990-06-01

    Enucleated human polymorphonuclear leukocytes (PMN cytoplasts), which have no nuclei and only a few granules, retain many of the functions of intact neutrophils. To better define the mechanisms and intracellular sites of antimicrobial agent accumulation in human neutrophils, we studied the antibiotic uptake process in PMN cytoplasts. Entry of eight radiolabeled antibiotics into PMN cytoplasts was determined by means of a velocity gradient centrifugation technique. Uptakes of these antibiotics by cytoplasts were compared with our findings in intact PMN. Penicillin entered both intact PMN and cytoplasts poorly. Metronidazole achieved a concentration in cytoplasts (and PMN) equal to or somewhat less than the extracellular concentration. Chloramphenicol, a lipid-soluble drug, and trimethoprim were concentrated three- to fourfold by cytoplasts. An unusual finding was that trimethroprim, unlike other tested antibiotics, was accumulated by cytoplasts more readily at 25 degrees C than at 37 degrees C. After an initial rapid association with cytoplasts, cell-associated imipenem declined progressively with time. Clindamycin and two macrolide antibiotics (roxithromycin, erythromycin) were concentrated 7- to 14-fold by cytoplasts. This indicates that cytoplasmic granules are not essential for accumulation of these drugs. Adenosine inhibited cytoplast uptake of clindamycin, which enters intact phagocytic cells by the membrane nucleoside transport system. Roxithromycin uptake by cytoplasts was inhibited by phagocytosis, which may reduce the number of cell membrane sites available for the transport of macrolides. These studies have added to our understanding of uptake mechanisms for antibiotics which are highly concentrated in phagocytes.

  18. Antibiotic Bactericidal Activity Is Countered by Maintaining pH Homeostasis in Mycobacterium smegmatis.

    PubMed

    Bartek, I L; Reichlen, M J; Honaker, R W; Leistikow, R L; Clambey, E T; Scobey, M S; Hinds, A B; Born, S E; Covey, C R; Schurr, M J; Lenaerts, A J; Voskuil, M I

    2016-01-01

    Antibiotics target specific biosynthetic processes essential for bacterial growth. It is intriguing that several commonalities connect the bactericidal activity of seemingly disparate antibiotics, such as the numerous conditions that confer broad-spectrum antibiotic tolerance. Whether antibiotics kill in a manner unique to their specific targets or by a universal mechanism is a critical and contested subject. Herein, we demonstrate that the bactericidal activity of diverse antibiotics against Mycobacterium smegmatis and four evolutionarily divergent bacterial pathogens was blocked by conditions that worked to maintain intracellular pH homeostasis. Single-cell pH analysis demonstrated that antibiotics increased the cytosolic pH of M. smegmatis, while conditions that promoted proton entry into the cytosol prevented intracellular alkalization and antibiotic killing. These findings led to a hypothesis that posits antibiotic lethality occurs when antibiotics obstruct ATP-consuming biosynthetic processes while metabolically driven proton efflux is sustained despite the loss of proton influx via ATP synthase. Consequently, without a concomitant reduction in respiratory proton efflux, cell death occurs due to intracellular alkalization. Our findings indicate the effects of antibiotics on pH homeostasis should be considered a potential mechanism contributing to antibiotic lethality. IMPORTANCE Since the discovery of antibiotics, mortality due to bacterial infection has decreased dramatically. However, infections from difficult to treat bacteria such as Mycobacterium tuberculosis and multidrug-resistant pathogens have been on the rise. An understanding of the cascade of events that leads to cell death downstream of specific drug-target interactions is not well understood. We have discovered that killing by several classes of antibiotics was stopped by maintaining pH balance within the bacterial cell, consistent with a shared mechanism of antibiotic killing. Our findings

  19. The Antibiotic Resistance Problem Revisited

    ERIC Educational Resources Information Center

    Lawson, Michael A.

    2008-01-01

    The term "antibiotic" was first proposed by Vuillemin in 1889 but was first used in the current sense by Walksman in 1941. An antibiotic is defined as a "derivative produced by the metabolism of microorganisms that possess antibacterial activity at low concentrations and is not toxic to the host." In this article, the author describes how…

  20. Do we need new antibiotics?

    PubMed

    Rolain, J-M; Abat, C; Jimeno, M-T; Fournier, P-E; Raoult, D

    2016-05-01

    For several years, alarmist articles both in mass media and in the scientific community have reported an increase in antibiotic resistance, even citing an inability to treat patients infected with multidrug-resistant bacteria (MDR) responsible for high mortality worldwide. In this review we summarize and discuss the key points associated with the reality of (i) the existence of pandrug-resistant bacteria, (ii) the increase of resistance worldwide, (iii) the link between resistance and death, and (iv) the need to develop new antibiotics. Data on antibiotic resistance in Europe for the main bacteria associated with invasive infections apparently demonstrate that apart from Klebsiella pneumoniae, which is resistant to carbapenems in three countries (Romania, Italy and Greece), the level of resistance to three or more classes of antibiotics (defined as MDR phenotype) has remained low and stable over the last 5 years and that therapeutic options exist both for reference antibiotics and for old antibiotics. The clinical outcome of patients infected by MDR bacteria remains controversial and death rates attributable to MDR bacteria versus non-MDR bacteria are still debated. The arsenal of antibiotics currently available (including 'old antibiotics') suffices for facing the waves of emergence of new bacterial resistance and should be considered as a World Heritage. This heritage should be managed in a non-profit model with international regulatory approval. PMID:27021418

  1. Antibiotic use in livestock production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antibiotic usage is a useful and commonly implemented practice in livestock and production agriculture that has progressively gained attention in recent years from consumers of animal products due to concerns about human and environmental health. Sub-therapeutic usage of antibiotics has led to a con...

  2. Stress-induced antibiotic susceptibility testing on a chip.

    PubMed

    Kalashnikov, Maxim; Campbell, Jennifer; Lee, Jean C; Sharon, Andre; Sauer-Budge, Alexis F

    2014-01-08

    We have developed a rapid microfluidic method for antibiotic susceptibility testing in a stress-based environment. Fluid is passed at high speeds over bacteria immobilized on the bottom of a microfluidic channel. In the presence of stress and antibiotic, susceptible strains of bacteria die rapidly. However, resistant bacteria survive these stressful conditions. The hypothesis behind this method is new: stress activation of biochemical pathways, which are targets of antibiotics, can accelerate antibiotic susceptibility testing. As compared to standard antibiotic susceptibility testing methods, the rate-limiting step - bacterial growth - is omitted during antibiotic application. The technical implementation of the method is in a combination of standard techniques and innovative approaches. The standard parts of the method include bacterial culture protocols, defining microfluidic channels in polydimethylsiloxane (PDMS), cell viability monitoring with fluorescence, and batch image processing for bacteria counting. Innovative parts of the method are in the use of culture media flow for mechanical stress application, use of enzymes to damage but not kill the bacteria, and use of microarray substrates for bacterial attachment. The developed platform can be used in antibiotic and nonantibiotic related drug development and testing. As compared to the standard bacterial suspension experiments, the effect of the drug can be turned on and off repeatedly over controlled time periods. Repetitive observation of the same bacterial population is possible over the course of the same experiment.

  3. [Antibiotic resistance: A global crisis].

    PubMed

    Alós, Juan-Ignacio

    2015-12-01

    The introduction of antibiotics into clinical practice represented one of the most important interventions for the control of infectious diseases. Antibiotics have saved millions of lives and have also brought a revolution in medicine. However, an increasing threat has deteriorated the effectiveness of these drugs, that of bacterial resistance to antibiotics, which is defined here as the ability of bacteria to survive in antibiotic concentrations that inhibit/kill others of the same species. In this review some recent and important examples of resistance in pathogens of concern for mankind are mentioned. It is explained, according to present knowledge, the process that led to the current situation in a short time, evolutionarily speaking. It begins with the resistance genes, continues with clones and genetic elements involved in the maintenance and dissemination, and ends with other factors that contribute to its spread. Possible responses to the problem are also reviewed, with special reference to the development of new antibiotics.

  4. Antibiotics, microbiota, and immune defense.

    PubMed

    Ubeda, Carles; Pamer, Eric G

    2012-09-01

    The gastrointestinal tract microbiota contributes to the development and differentiation of the mammalian immune system. The composition of the microbiota affects immune responses and affects susceptibility to infection by intestinal pathogens and development of allergic and inflammatory bowel diseases. Antibiotic administration, while facilitating clearance of targeted infections, also perturbs commensal microbial communities and decreases host resistance to antibiotic-resistant microbes. Here, we review recent advances that begin to define the interactions between complex intestinal microbial populations and the mammalian immune system and how this relation is perturbed by antibiotic administration. We further discuss how antibiotic-induced disruption of the microbiota and immune homeostasis can lead to disease and we review strategies to restore immune defenses during antibiotic administration.

  5. The Prehistory of Antibiotic Resistance.

    PubMed

    Perry, Julie; Waglechner, Nicholas; Wright, Gerard

    2016-01-01

    Antibiotic resistance is a global problem that is reaching crisis levels. The global collection of resistance genes in clinical and environmental samples is the antibiotic "resistome," and is subject to the selective pressure of human activity. The origin of many modern resistance genes in pathogens is likely environmental bacteria, including antibiotic producing organisms that have existed for millennia. Recent work has uncovered resistance in ancient permafrost, isolated caves, and in human specimens preserved for hundreds of years. Together with bioinformatic analyses on modern-day sequences, these studies predict an ancient origin of resistance that long precedes the use of antibiotics in the clinic. Understanding the history of antibiotic resistance is important in predicting its future evolution. PMID:27252395

  6. Colistin: Revival of an Old Polymyxin Antibiotic.

    PubMed

    Dijkmans, Anneke C; Wilms, Erik B; Kamerling, Ingrid M C; Birkhoff, Willem; Ortiz-Zacarías, Natalia V; van Nieuwkoop, Cees; Verbrugh, Henri A; Touw, Daan J

    2015-08-01

    Colistin (polymyxin E) is a positively charged deca-peptide antibiotic that disrupts the integrity of the outer membrane of the cell wall of gram-negative bacteria by binding to the lipid A moiety of lipopolysaccharides, resulting in cell death. The endotoxic activity of lipopolysaccharides is simultaneously inhibited. Colistin is increasingly being prescribed as rescue treatment for infections with multidrug-resistant bacilli. Nephrotoxicity and, to a lesser degree, neurotoxicity occur often during systemic colistin therapy, and have severely limited its application in the past. However, these side effects are largely reversible and can be managed through close monitoring. The prodrug colistimethate sodium (CMS) is less toxic and is, therefore, the preferred formulation for parenteral administration. Importantly, resistance to colistin seems to emerge often unless it is combined with another antibiotic, but further studies into this phenomenon are necessary. Pharmacokinetic and pharmacodynamic properties have received little attention, partly because of the physicochemical peculiarities of polymyxin antibiotics, especially their propensity to stick to other molecules and surfaces. The ratio between the area under the curve of free colistin and the pathogen's Minimal Inhibitory Concentration (MIC) best predicts microbiological and clinical responses, but more studies are needed in this area. Likewise, further standardization is needed in production and labeling of colistin formulations, and in the way the susceptibility of bacteria to colistin is determined.

  7. Mildiomycin: a nucleoside antibiotic that inhibits protein synthesis.

    PubMed

    Feduchi, E; Cosín, M; Carrasco, L

    1985-03-01

    Mildiomycin, a new nucleoside antibiotic, selectively inhibits protein synthesis in HeLa cells, and is less active in the inhibition of RNA or DNA synthesis. An increased inhibition of translation by mildiomycin is observed in cultured HeLa cells when they are permeabilized by encephalomyocarditis virus. This observation suggests that this antibiotic does not easily pass through the cell membrane, as occurs with other nucleoside and aminoglycoside antibiotics. The inhibition of translation is also observed in cell-free systems, such as endogenous protein synthesis in a rabbit reticulocyte lysate or the synthesis of polyphenylalanine directed by poly (U). Finally the mode of action of mildiomycin was investigated and the results suggest that the compound blocks the peptidyl-transferase center.

  8. Semi-stochastic cell-level computational modeling of the immune system response to bacterial infections and the effects of antibiotics.

    PubMed

    Vermolen, F J; Mul, M M; Gefen, A

    2014-08-01

    A mathematical model for the immune system response to bacterial infections is proposed. The formalism is based on modeling the chemokine-determined transmigration of leukocytes from a venule through the venule walls and the subsequent in-tissue migration and engulfment of the pathogens that are responsible for the infection. The model is based on basic principles, such as Poiseuille blood flow through the venule, fundamental solutions of the diffusion-reaction equation for the concentration field of pathogen-released chemokines, linear chemotaxis of the leukocytes, random walk of pathogens, and stochastic processes for the death and division of pathogens. Thereby, a computationally tractable and, as far as we know, original framework has been obtained, which is used to incorporate the interaction of a substantial number of leukocytes and thereby to unravel the significance of biological processes and parameters regarding the immune system response. The developed model provides a neat way for visualization of the biophysical mechanism of the immune system response. The simulations indicate a weak correlation between the immune system response in terms of bacterial clearing time and the leukocyte stiffness, and a significant decrease in the clearing time with increasing in-blood leukocyte density, decreasing pathogen motility, and increasing venule wall transmissivity. Finally, the increase in the pathogen death rate and decrease in pathogen motility induce a decrease in the clearing time of the infection. The adjustment of the latter two quantities mimic the administration of antibiotics.

  9. Comet assay with gill cells of Mytilus galloprovincialis end point tools for biomonitoring of water antibiotic contamination: Biological treatment is a reliable process for detoxification.

    PubMed

    Mustapha, Nadia; Zouiten, Amina; Dridi, Dorra; Tahrani, Leyla; Zouiten, Dorra; Mosrati, Ridha; Cherif, Ameur; Chekir-Ghedira, Leila; Mansour, Hedi Ben

    2016-04-01

    This article investigates the ability of Pseudomonas peli to treat industrial pharmaceuticals wastewater (PW). Liquid chromatography-mass spectrometry (MS)/MS analysis revealed the presence, in this PW, of a variety of antibiotics such as sulfathiazole, sulfamoxole, norfloxacine, cloxacilline, doxycycline, and cefquinome.P. peli was very effective to be grown in PW and inducts a remarkable increase in chemical oxygen demand and biochemical oxygen demand (140.31 and 148.51%, respectively). On the other hand, genotoxicity of the studied effluent, before and after 24 h of shaking incubation with P. peli, was evaluated in vivo in the Mediterranean wild mussels Mytilus galloprovincialis using comet assay for quantification of DNA fragmentation. Results show that PW exhibited a statistically significant (p< 0.001) genotoxic effect in a dose-dependent manner; indeed, the percentage of genotoxicity was 122.6 and 49.5% after exposure to 0.66 ml/kg body weight (b.w.); 0.33 ml/kg b.w. of PW, respectively. However, genotoxicity decreased strongly when tested with the PW obtained after incubation with P. peli We can conclude that using comet assay genotoxicity end points are useful tools to biomonitor the physicochemical and biological quality of water. Also, it could be concluded that P. peli can treat and detoxify the studied PW.

  10. Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature.

    PubMed

    Hiramatsu, Keiichi; Igarashi, Masayuki; Morimoto, Yuh; Baba, Tadashi; Umekita, Maya; Akamatsu, Yuzuru

    2012-06-01

    By screening cultures of soil bacteria, we re-discovered an old antibiotic (nybomycin) as an antibiotic with a novel feature. Nybomycin is active against quinolone-resistant Staphylococcus aureus strains with mutated gyrA genes but not against those with intact gyrA genes against which quinolone antibiotics are effective. Nybomycin-resistant mutant strains were generated from a quinolone-resistant, nybomycin-susceptible, vancomycin-intermediate S. aureus (VISA) strain Mu 50. The mutants, occurring at an extremely low rate (<1 × 10(-11)/generation), were found to have their gyrA genes back-mutated and to have lost quinolone resistance. Here we describe nybomycin as the first member of a novel class of antibiotics designated 'reverse antibiotics'. PMID:22534508

  11. Antibiotic Bactericidal Activity Is Countered by Maintaining pH Homeostasis in Mycobacterium smegmatis

    PubMed Central

    Bartek, I. L.; Reichlen, M. J.; Honaker, R. W.; Leistikow, R. L.; Clambey, E. T.; Scobey, M. S.; Hinds, A. B.; Born, S. E.; Covey, C. R.; Schurr, M. J.; Lenaerts, A. J.

    2016-01-01

    ABSTRACT Antibiotics target specific biosynthetic processes essential for bacterial growth. It is intriguing that several commonalities connect the bactericidal activity of seemingly disparate antibiotics, such as the numerous conditions that confer broad-spectrum antibiotic tolerance. Whether antibiotics kill in a manner unique to their specific targets or by a universal mechanism is a critical and contested subject. Herein, we demonstrate that the bactericidal activity of diverse antibiotics against Mycobacterium smegmatis and four evolutionarily divergent bacterial pathogens was blocked by conditions that worked to maintain intracellular pH homeostasis. Single-cell pH analysis demonstrated that antibiotics increased the cytosolic pH of M. smegmatis, while conditions that promoted proton entry into the cytosol prevented intracellular alkalization and antibiotic killing. These findings led to a hypothesis that posits antibiotic lethality occurs when antibiotics obstruct ATP-consuming biosynthetic processes while metabolically driven proton efflux is sustained despite the loss of proton influx via ATP synthase. Consequently, without a concomitant reduction in respiratory proton efflux, cell death occurs due to intracellular alkalization. Our findings indicate the effects of antibiotics on pH homeostasis should be considered a potential mechanism contributing to antibiotic lethality. IMPORTANCE Since the discovery of antibiotics, mortality due to bacterial infection has decreased dramatically. However, infections from difficult to treat bacteria such as Mycobacterium tuberculosis and multidrug-resistant pathogens have been on the rise. An understanding of the cascade of events that leads to cell death downstream of specific drug-target interactions is not well understood. We have discovered that killing by several classes of antibiotics was stopped by maintaining pH balance within the bacterial cell, consistent with a shared mechanism of antibiotic killing. Our

  12. How antibiotics kill bacteria: from targets to networks

    PubMed Central

    Kohanski, Michael A; Dwyer, Daniel J; Collins, James J

    2010-01-01

    Preface Antibiotic drug-target interactions, and their respective direct effects, are generally well-characterized. In contrast, the bacterial responses to antibiotic drug treatments that contribute to cell death are not as well understood and have proven to be quite complex, involving multiple genetic and biochemical pathways. Here, we review the multi-layered effects of drug-target interactions, including the essential cellular processes inhibited by bactericidal antibiotics and the associated cellular response mechanisms that contribute to killing by bactericidal antibiotics. We also discuss new insights into these mechanisms that have been revealed through the study of biological networks, and describe how these insights, together with related developments in synthetic biology, may be exploited to create novel antibacterial therapies. PMID:20440275

  13. Bacterial Protein Synthesis as a Target for Antibiotic Inhibition.

    PubMed

    Arenz, Stefan; Wilson, Daniel N

    2016-01-01

    Protein synthesis occurs on macromolecular machines, called ribosomes. Bacterial ribosomes and the translational machinery represent one of the major targets for antibiotics in the cell. Therefore, structural and biochemical investigations into ribosome-targeting antibiotics provide not only insight into the mechanism of action and resistance of antibiotics, but also insight into the fundamental process of protein synthesis. This review summarizes the recent advances in our understanding of protein synthesis, particularly with respect to X-ray and cryoelectron microscopy (cryo-EM) structures of ribosome complexes, and highlights the different steps of translation that are targeted by the diverse array of known antibiotics. Such findings will be important for the ongoing development of novel and improved antimicrobial agents to combat the rapid emergence of multidrug resistant pathogenic bacteria. PMID:27481773

  14. A new antibiotic kills pathogens without detectable resistance.

    PubMed

    Ling, Losee L; Schneider, Tanja; Peoples, Aaron J; Spoering, Amy L; Engels, Ina; Conlon, Brian P; Mueller, Anna; Schäberle, Till F; Hughes, Dallas E; Epstein, Slava; Jones, Michael; Lazarides, Linos; Steadman, Victoria A; Cohen, Douglas R; Felix, Cintia R; Fetterman, K Ashley; Millett, William P; Nitti, Anthony G; Zullo, Ashley M; Chen, Chao; Lewis, Kim

    2015-01-22

    Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance. PMID:25561178

  15. Environmental and Public Health Implications of Water Reuse: Antibiotics, Antibiotic Resistant Bacteria, and Antibiotic Resistance Genes.

    PubMed

    Hong, Pei-Ying; Al-Jassim, Nada; Ansari, Mohd Ikram; Mackie, Roderick I

    2013-01-01

    Water scarcity is a global problem, and is particularly acute in certain regions like Africa, the Middle East, as well as the western states of America. A breakdown on water usage revealed that 70% of freshwater supplies are used for agricultural irrigation. The use of reclaimed water as an alternative water source for agricultural irrigation would greatly alleviate the demand on freshwater sources. This paradigm shift is gaining momentum in several water scarce countries like Saudi Arabia. However, microbial problems associated with reclaimed water may hinder the use of reclaimed water for agricultural irrigation. Of particular concern is that the occurrence of antibiotic residues in the reclaimed water can select for antibiotic resistance genes among the microbial community. Antibiotic resistance genes can be associated with mobile genetic elements, which in turn allow a promiscuous transfer of resistance traits from one bacterium to another. Together with the pathogens that are present in the reclaimed water, antibiotic resistant bacteria can potentially exchange mobile genetic elements to create the "perfect microbial storm". Given the significance of this issue, a deeper understanding of the occurrence of antibiotics in reclaimed water, and their potential influence on the selection of resistant microorganisms would be essential. In this review paper, we collated literature over the past two decades to determine the occurrence of antibiotics in municipal wastewater and livestock manure. We then discuss how these antibiotic resistant bacteria may impose a potential microbial risk to the environment and public health, and the knowledge gaps that would have to be addressed in future studies. Overall, the collation of the literature in wastewater treatment and agriculture serves to frame and identify potential concerns with respect to antibiotics, antibiotic resistant bacteria, and antibiotic resistance genes in reclaimed water.

  16. Environmental and Public Health Implications of Water Reuse: Antibiotics, Antibiotic Resistant Bacteria, and Antibiotic Resistance Genes

    PubMed Central

    Hong, Pei-Ying; Al-Jassim, Nada; Ansari, Mohd Ikram; Mackie, Roderick I.

    2013-01-01

    Water scarcity is a global problem, and is particularly acute in certain regions like Africa, the Middle East, as well as the western states of America. A breakdown on water usage revealed that 70% of freshwater supplies are used for agricultural irrigation. The use of reclaimed water as an alternative water source for agricultural irrigation would greatly alleviate the demand on freshwater sources. This paradigm shift is gaining momentum in several water scarce countries like Saudi Arabia. However, microbial problems associated with reclaimed water may hinder the use of reclaimed water for agricultural irrigation. Of particular concern is that the occurrence of antibiotic residues in the reclaimed water can select for antibiotic resistance genes among the microbial community. Antibiotic resistance genes can be associated with mobile genetic elements, which in turn allow a promiscuous transfer of resistance traits from one bacterium to another. Together with the pathogens that are present in the reclaimed water, antibiotic resistant bacteria can potentially exchange mobile genetic elements to create the “perfect microbial storm”. Given the significance of this issue, a deeper understanding of the occurrence of antibiotics in reclaimed water, and their potential influence on the selection of resistant microorganisms would be essential. In this review paper, we collated literature over the past two decades to determine the occurrence of antibiotics in municipal wastewater and livestock manure. We then discuss how these antibiotic resistant bacteria may impose a potential microbial risk to the environment and public health, and the knowledge gaps that would have to be addressed in future studies. Overall, the collation of the literature in wastewater treatment and agriculture serves to frame and identify potential concerns with respect to antibiotics, antibiotic resistant bacteria, and antibiotic resistance genes in reclaimed water. PMID:27029309

  17. Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease.

    PubMed

    Holler, Ernst; Butzhammer, Peter; Schmid, Karin; Hundsrucker, Christian; Koestler, Josef; Peter, Katrin; Zhu, Wentao; Sporrer, Daniela; Hehlgans, Thomas; Kreutz, Marina; Holler, Barbara; Wolff, Daniel; Edinger, Matthias; Andreesen, Reinhard; Levine, John E; Ferrara, James L; Gessner, Andre; Spang, Rainer; Oefner, Peter J

    2014-05-01

    Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.

  18. Quinolones: from antibiotics to autoinducers

    PubMed Central

    Heeb, Stephan; Fletcher, Matthew P; Chhabra, Siri Ram; Diggle, Stephen P; Williams, Paul; Cámara, Miguel

    2011-01-01

    Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc1 complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression. PMID:20738404

  19. Effects of residual antibiotics in groundwater on Salmonella typhimurium: changes in antibiotic resistance, in vivo and in vitro pathogenicity.

    PubMed

    Haznedaroglu, Berat Z; Yates, Marylynn V; Maduro, Morris F; Walker, Sharon L

    2012-01-01

    An outbreak-causing strain of Salmonella enterica serovar Typhimurium was exposed to groundwater with residual antibiotics for up to four weeks. Representative concentrations (0.05, 1, and 100 μg L(-1)) of amoxicillin, tetracycline, and a mixture of several other antibiotics (1 μg L(-1) each) were spiked into artificially prepared groundwater (AGW). Antibiotic susceptibility analysis and the virulence response of stressed Salmonella were determined on a weekly basis by using human epithelial cells (HEp2) and soil nematodes (C. elegans). Results have shown that Salmonella typhimurium remains viable for long periods of exposure to antibiotic-supplemented groundwater; however, they failed to cultivate as an indication of a viable but nonculturable state. Prolonged antibiotics exposure did not induce any changes in the antibiotic susceptibility profile of the S. typhimurium strain used in this study. S. typhimurium exposed to 0.05 and 1 μg L(-1) amoxicillin, and 1 μg L(-1) tetracycline showed hyper-virulent profiles in both in vitro and in vivo virulence assays with the HEp2 cells and C. elegans respectively, most evident following 2nd and 3rd weeks of exposure. PMID:22051852

  20. Antibiotic resistance in wild birds

    PubMed Central

    Bonnedahl, Jonas

    2014-01-01

    Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance. PMID:24697355

  1. Systemic antibiotic therapy in periodontics

    PubMed Central

    Kapoor, Anoop; Malhotra, Ranjan; Grover, Vishakha; Grover, Deepak

    2012-01-01

    Systemic antibiotics in conjunction with scaling and root planing (SRP), can offer an additional benefit over SRP alone in the treatment of periodontitis, in terms of clinical attachment loss (CAL) and pocket depth change, and reduced risk of additional CAL loss. However, antibiotics are not innocuous drugs. Their use should be justified on the basis of a clearly established need and should not be substituted for adequate local treatment. The aim of this review is to discuss the rationale, proper selection, dosage and duration for antibiotic therapy so as to optimize the usefulness of drug therapy. PMID:23559912

  2. Antibiotic Treatment of Hidradenitis Suppurativa.

    PubMed

    Bettoli, Vincenzo; Join-Lambert, Olivier; Nassif, Aude

    2016-01-01

    Although hidradenitis suppurativa (HS) is not primarily an infectious disease, antibiotics are widely used to treat HS. Recent microbiological data show that HS suppurating lesions are associated with a polymorphous anaerobic flora, including actinomycetes and milleri group streptococci, and can therefore be considered as polymicrobial soft tissue and skin infections. Analysis of the literature provides little information on the efficacy of antibiotics in HS but suggests a beneficial effect of certain antimicrobial treatments, depending on the clinical severity of the disease. Patients must be informed and should agree with the treatment strategy before starting antibiotic treatments.

  3. Antibiotic resistance in wild birds.

    PubMed

    Bonnedahl, Jonas; Järhult, Josef D

    2014-05-01

    Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance. PMID:24697355

  4. Inhibition of intracellular growth of Listeria monocytogenes by antibiotics.

    PubMed Central

    Michelet, C; Avril, J L; Cartier, F; Berche, P

    1994-01-01

    We studied the activities of 15 antibiotics on the intracellular growth of Listeria monocytogenes in a HeLa cell line. After 24 h of contact with the infected cells, the antibiotics most effective against the intracellular growth of the 10 strains tested were amoxicillin, temafloxacin, and sparfloxacin, which nevertheless failed to totally eliminate the intracellular bacteria. Rifampin and co-trimoxazole had variable effects, depending on the isolates studied. The most active combinations were amoxicillin-sparfloxacin, co-trimoxazole-gentamicin, and sparfloxacin-co-trimoxazole. The results suggest the value of using a cell culture technique to study the activities of antibiotics against certain bacteria with intracellular sites of multiplication. PMID:8203836

  5. Treatment with antibiotics that interfere with peptidoglycan biosynthesis inhibits chloroplast division in the desmid Closterium.

    PubMed

    Matsumoto, Hiroko; Takechi, Katsuaki; Sato, Hiroshi; Takio, Susumu; Takano, Hiroyoshi

    2012-01-01

    Charophytes is a green algal group closely related to land plants. We investigated the effects of antibiotics that interfere with peptidoglycan biosynthesis on chloroplast division in the desmid Closterium peracerosum-strigosum-littorale complex. To detect cells just after division, we used colchicine, which inhibits Closterium cell elongation after division. Although normal Closterium cells had two chloroplasts before and after cell division, cells treated with ampicillin, D-cycloserine, or fosfomycin had only one chloroplast after cell division, suggesting that the cells divided without chloroplast division. The antibiotics bacitracin and vancomycin showed no obvious effect. Electron microscopic observation showed that irregular-shaped chloroplasts existed in ampicillin-treated Closterium cells. Because antibiotic treatments resulted in the appearance of long cells with irregular chloroplasts and cell death, we counted cell types in the culture. The results suggested that cells with one chloroplast appeared first and then a huge chloroplast was generated that inhibited cell division, causing elongation followed by cell death.

  6. Treatment with Antibiotics that Interfere with Peptidoglycan Biosynthesis Inhibits Chloroplast Division in the Desmid Closterium

    PubMed Central

    Matsumoto, Hiroko; Takechi, Katsuaki; Sato, Hiroshi; Takio, Susumu; Takano, Hiroyoshi

    2012-01-01

    Charophytes is a green algal group closely related to land plants. We investigated the effects of antibiotics that interfere with peptidoglycan biosynthesis on chloroplast division in the desmid Closterium peracerosum–strigosum–littorale complex. To detect cells just after division, we used colchicine, which inhibits Closterium cell elongation after division. Although normal Closterium cells had two chloroplasts before and after cell division, cells treated with ampicillin, D-cycloserine, or fosfomycin had only one chloroplast after cell division, suggesting that the cells divided without chloroplast division. The antibiotics bacitracin and vancomycin showed no obvious effect. Electron microscopic observation showed that irregular-shaped chloroplasts existed in ampicillin-treated Closterium cells. Because antibiotic treatments resulted in the appearance of long cells with irregular chloroplasts and cell death, we counted cell types in the culture. The results suggested that cells with one chloroplast appeared first and then a huge chloroplast was generated that inhibited cell division, causing elongation followed by cell death. PMID:22815801

  7. Selective condensation of DNA by aminoglycoside antibiotics.

    PubMed

    Kopaczynska, M; Schulz, A; Fraczkowska, K; Kraszewski, S; Podbielska, H; Fuhrhop, J H

    2016-05-01

    The condensing effect of aminoglycoside antibiotics on the structure of double-stranded DNA was examined. The selective condensation of DNA by small molecules is an interesting approach in biotechnology. Here, we present the interaction between calf thymus DNA and three types of antibiotic molecules: tobramycin, kanamycin, and neomycin. Several techniques were applied to study this effect. Atomic force microscopy, transmission electron microscopy images, and nuclear magnetic resonance spectra showed that the interaction of tobramycin with double-stranded DNA caused the rod, toroid, and sphere formation and very strong condensation of DNA strands, which was not observed in the case of other aminoglycosides used in the experiment. Studies on the mechanisms by which small molecules interact with DNA are important in understanding their functioning in cells, in designing new and efficient drugs, or in minimizing their adverse side effects. Specific interactions between tobramycin and DNA double helix was modeled using molecular dynamics simulations. Simulation study shows the aminoglycoside specificity to bend DNA double helix, shedding light on the origins of toroid formation. This phenomenon may lighten the ototoxicity or nephrotoxicity issues, but also other adverse reactions of aminoglycoside antibiotics in the human body.

  8. Novel targets for antibiotics--an update.

    PubMed

    Isaacson, R E

    1997-08-01

    The emergence of widespread antibiotic resistance as an impediment in the treatment of bacterial diseases is of growing concern. In some instances, clinicians are left with few or no antibiotics for treatment of infections and this problem will more than likely grow in magnitude. One approach to get around the problem of antibiotic resistance is to develop new drugs with novel targets and mechanisms of action. Due to the 'newness' of these novel targets as therapeutic targets, the likelihood that resistance will initially be widespread is low. Three approaches are discussed in this overview: discovery of new essential genes that are expressed exclusively in vivo development of compounds that act on global bacterial gene regulators; and interference with virulence determinants. By exploiting virulence related attributes or genes expressed exclusively in vivo, the risk of resistance is reduced since inhibiting these products will probably alter the ecology (habitats) of these organisms rather than causing direct cell death. This might also lead to a selective targeting of pathogens with the beneficial consequence of ignoring organisms growing in their normal habitat, such as in the gastrointestinal tract or skin.

  9. β-Lactam Antibiotics Renaissance

    PubMed Central

    Qin, Wenling; Panunzio, Mauro; Biondi, Stefano

    2014-01-01

    Since the 1940s β-lactam antibiotics have been used to treat bacterial infections. However, emergence and dissemination of β-lactam resistance has reached the point where many marketed β-lactams no longer are clinically effective. The increasing prevalence of multidrug-resistant bacteria and the progressive withdrawal of pharmaceutical companies from antibiotic research have evoked a strong reaction from health authorities, who have implemented initiatives to encourage the discovery of new antibacterials. Despite this gloomy scenario, several novel β-lactam antibiotics and β-lactamase inhibitors have recently progressed into clinical trials, and many more such compounds are being investigated. Here we seek to provide highlights of recent developments relating to the discovery of novel β-lactam antibiotics and β-lactamase inhibitors. PMID:27025744

  10. Antibiotic resistance: An ethical challenge.

    PubMed

    Littmann, Jasper; Buyx, Alena; Cars, Otto

    2015-10-01

    In this paper, we argue that antibiotic resistance (ABR) raises a number of ethical problems that have not yet been sufficiently addressed. We outline four areas in which ethical issues that arise in relation to ABR are particularly pressing. First, the emergence of multidrug-resistant and extensively drug-resistant infections exacerbates traditional ethical challenges of infectious disease control, such as the restriction of individual liberty for the protection of the public's health. Second, ABR raises issues of global distributive justice, both with regard to the overuse and lack of access to antibiotics. Third, the use of antibiotics in veterinary medicine raises serious concerns for animal welfare and sustainable farming practices. Finally, the diminishing effectiveness of antibiotics leads to questions about intergenerational justice and our responsibility for the wellbeing of future generations. We suggest that current policy discussions should take ethical conflicts into account and engage openly with the challenges that we outline in this paper.

  11. The Double Life of Antibiotics

    PubMed Central

    Yap, Mee-Ngan F.

    2013-01-01

    Antibiotic resistance is a persistent health care problem worldwide. Evidence for the negative consequences of subtherapeutic feeding in livestock production has been mounting while the antibiotic pipeline is drying up. In recent years, there has been a paradigm shift in our perception of antibiotics. Apart from its roles in self-defense, antibiotics also serve as inter-microbial signaling molecules, regulators of gene expression, microbial food sources, and as mediators of host immune response. “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under-dose himself and by exposing his microbes to nonlethal quantities of the drug make them resistant.”~Alexander Fleming PMID:24003650

  12. Prophylactic antibiotics in orthopaedic surgery.

    PubMed

    Prokuski, Laura; Clyburn, Terry A; Evans, Richard P; Moucha, Calin S

    2011-01-01

    The use of prophylactic antibiotics in orthopaedic surgery has been proven effective in reducing surgical site infections after hip and knee arthroplasty, spine procedures, and open reduction and internal fixation of fractures. To maximize the beneficial effect of prophylactic antibiotics, while minimizing any adverse effects, the correct antimicrobial agent must be selected, the drug must be administered just before incision, and the duration of administration should not exceed 24 hours.

  13. The pneumococcal cell envelope stress-sensing system LiaFSR is activated by murein hydrolases and lipid II-interacting antibiotics.

    PubMed

    Eldholm, Vegard; Gutt, Beatrice; Johnsborg, Ola; Brückner, Reinhold; Maurer, Patrick; Hakenbeck, Regine; Mascher, Thorsten; Håvarstein, Leiv Sigve

    2010-04-01

    In the Firmicutes, two-component regulatory systems of the LiaSR type sense and orchestrate the response to various agents that perturb cell envelope functions, in particular lipid II cycle inhibitors. In the current study, we found that the corresponding system in Streptococcus pneumoniae displays similar properties but, in addition, responds to cell envelope stress elicited by murein hydrolases. During competence for genetic transformation, pneumococci attack and lyse noncompetent siblings present in the same environment. This phenomenon, termed fratricide, increases the efficiency of horizontal gene transfer in vitro and is believed to stimulate gene exchange also under natural conditions. Lysis of noncompetent target cells is mediated by the putative murein hydrolase CbpD, the key effector of the fratricide mechanism, and the autolysins LytA and LytC. To avoid succumbing to their own lysins, competent attacker cells must possess a protective mechanism rendering them immune. The most important component of this mechanism is ComM, an integral membrane protein of unknown function that is expressed only in competent cells. Here, we show that a second layer of self-protection is provided by the pneumococcal LiaFSR system, which senses the damage inflicted to the cell wall by CbpD, LytA, and LytC. Two members of the LiaFSR regulon, spr0810 and PcpC (spr0351), were shown to contribute to the LiaFSR-coordinated protection against fratricide-induced self-lysis.

  14. Expedient antibiotics production: Final report

    SciTech Connect

    Bienkowski, P.R.; Byers, C.H.; Lee, D.D.

    1988-05-01

    The literature on the manufacture, separation and purification, and clinical uses of antibiotics was reviewed, and a bibliography of the pertinent material was completed. Five antimicrobial drugs, penicillin V and G, (and amoxicillin with clavulanic acid), Cephalexin (a cephalosporin), tetracycline and oxytetracycline, Bacitracin (topical), and sulfonamide (chemically produced) were identified for emergency production. Plants that manufacture antibiotics in the continental United States, Mexico, and Puerto Rico have been identified along with potential alternate sites such as those where SCP, enzyme, and fermentation ethanol are produced. Detailed process flow sheets and process descriptions have been derived from the literature and documented. This investigation revealed that a typical antibiotic-manufacturing facility is composed of two main sections: (1) a highly specialized, but generic, fermentation unit and (2) a multistep, complex separation and purification unit which is specific to a particular antibiotic product. The fermentation section requires specialized equipment for operation in a sterile environment which is not usually available in other industries. The emergency production of antibiotics under austere conditions will be feasible only if a substantial reduction in the complexity and degree of separation and purity normally required can be realized. Detailed instructions were developed to assist state and federal officials who would be directing the resumption of antibiotic production after a nuclear attack. 182 refs., 54 figs., 26 tabs.

  15. Enhancing the utility of existing antibiotics by targeting bacterial behaviour?

    PubMed Central

    Rogers, Geraint B; Carroll, Mary P; Bruce, Kenneth D

    2012-01-01

    The discovery of novel classes of antibiotics has slowed dramatically. This has occurred during a time when the appearance of resistant strains of bacteria has shown a substantial increase. Concern is therefore mounting over our ability to continue to treat infections in an effective manner using the antibiotics that are currently available. While ongoing efforts to discover new antibiotics are important, these must be coupled with strategies that aim to maintain as far as possible the spectrum of activity of existing antibiotics. In many instances, the resistance to antibiotics exhibited by bacteria in chronic infections is mediated not by direct resistance mechanisms, but by the adoption of modes of growth that confer reduced susceptibility. These include the formation of biofilms and the occurrence of subpopulations of ‘persister’ cells. As our understanding of these processes has increased, a number of new potential drug targets have been revealed. Here, advances in our ability to disrupt these systems that confer reduced susceptibility, and in turn increase the efficacy of antibiotic therapy, are discussed. PMID:21864314

  16. A new antibiotic with potent activity targets MscL.

    PubMed

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-07-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.

  17. A new antibiotic with potent activity targets MscL

    PubMed Central

    Iscla, Irene; Wray, Robin; Blount, Paul; Larkins-Ford, Jonah; Conery, Annie L; Ausubel, Frederick M; Ramu, Soumya; Kavanagh, Angela; Huang, Johnny X; Blaskovich, Mark A; Cooper, Matthew A; Obregon-Henao, Andres; Orme, Ian; Tjandra, Edwin S; Stroeher, Uwe H; Brown, Melissa H; Macardle, Cindy; van Holst, Nick; Ling Tong, Chee; Slattery, Ashley D; Gibson, Christopher T; Raston, Colin L; Boulos, Ramiz A

    2015-01-01

    The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections. PMID:25649856

  18. [Surviving Forms in Antibiotic-Treated Pseudomonas aeruginosa].

    PubMed

    Mulyukin, A L; Kozlova, A N; Sorokin, V V; Suzina, N E; Cherdyntseva, T A; Kotova, I B; Gaponov, A M; Tutel'yan, A V; El'-Registan, G I

    2015-01-01

    Survival of bacterial populations treated with lethal doses of antibiotics is ensured by the presence of very small numbers of persister cells. Unlike antibiotic-resistant cells, antibiotic tolerance of persisters is not inheritable and reversible. The present work provides evidence supporting the hypothesis of transformation (maturation) of persisters of an opportunistic pathogen Pseudomonas aeruginosa revealed by ciprofloxacin (CF) treatment (25-100 μg/mL) into dormant cystlike cells (CLC) and non-culturable cells (NC), as was described previously for a number. of non-spore-forming bacteria. Subpopulations of type 1 and type 2 persisters, which survived antibiotic treatment and developed into dormant forms, were heterogeneous in their capacity to form colonies or microcolonies upon germination, in resistance to heating at 70 degrees C, and in cell morphology Type 1 persisters, which were formed after 1-month incubation in the stationary-phase cultures in the medium with decreased C and N concentrations, developed in several types of surviving cells, including those similar to CLC in cell morphology. In the course of 1-month incubation of type 2 persisters, which were formed in exponentially growing cultures, other types of surviving cells developed: immature CLC and L-forms. Unlike P. aeruginosa CLC formed in the control post-stationary phase cultures without antibiotic treatment, most of 1-month persisters, especially type 2 ones, were characterized by the loss of colony-forming capacity, probably due to transition into an uncultured state with relatively high numbers of live intact cells (Live/Dead test). Another survival strategy of P. aeruginosa populations was ensured by a minor subpopulation of CF-tolerant and CF-resistant cells able to grow in the form of microcolonies or regular colonies of decreased size in the presence of the antibiotic. The described P. aeruginosa dormant forms may be responsible for persistent forms in bacteria carriers and latent

  19. [Surviving Forms in Antibiotic-Treated Pseudomonas aeruginosa].

    PubMed

    Mulyukin, A L; Kozlova, A N; Sorokin, V V; Suzina, N E; Cherdyntseva, T A; Kotova, I B; Gaponov, A M; Tutel'yan, A V; El'-Registan, G I

    2015-01-01

    Survival of bacterial populations treated with lethal doses of antibiotics is ensured by the presence of very small numbers of persister cells. Unlike antibiotic-resistant cells, antibiotic tolerance of persisters is not inheritable and reversible. The present work provides evidence supporting the hypothesis of transformation (maturation) of persisters of an opportunistic pathogen Pseudomonas aeruginosa revealed by ciprofloxacin (CF) treatment (25-100 μg/mL) into dormant cystlike cells (CLC) and non-culturable cells (NC), as was described previously for a number. of non-spore-forming bacteria. Subpopulations of type 1 and type 2 persisters, which survived antibiotic treatment and developed into dormant forms, were heterogeneous in their capacity to form colonies or microcolonies upon germination, in resistance to heating at 70 degrees C, and in cell morphology Type 1 persisters, which were formed after 1-month incubation in the stationary-phase cultures in the medium with decreased C and N concentrations, developed in several types of surviving cells, including those similar to CLC in cell morphology. In the course of 1-month incubation of type 2 persisters, which were formed in exponentially growing cultures, other types of surviving cells developed: immature CLC and L-forms. Unlike P. aeruginosa CLC formed in the control post-stationary phase cultures without antibiotic treatment, most of 1-month persisters, especially type 2 ones, were characterized by the loss of colony-forming capacity, probably due to transition into an uncultured state with relatively high numbers of live intact cells (Live/Dead test). Another survival strategy of P. aeruginosa populations was ensured by a minor subpopulation of CF-tolerant and CF-resistant cells able to grow in the form of microcolonies or regular colonies of decreased size in the presence of the antibiotic. The described P. aeruginosa dormant forms may be responsible for persistent forms in bacteria carriers and latent

  20. High Concentration of Red Clay as an Alternative for Antibiotics in Aquaculture.

    PubMed

    Jung, Jaejoon; Jee, Seung Cheol; Sung, Jung-Suk; Park, Woojun

    2016-01-01

    The use of antibiotics in aquaculture raises environmental and food safety concerns because chronic exposure of an aquatic ecosystem to antibiotics can result in the spread of antibiotic resistance, bioaccumulation of antibiotics in the organisms, and transfer of antibiotics to humans. In an attempt to overcome these problems, high-concentration red clay was applied as an alternative antibiotic against the following common fish pathogens: Aeromonas salmonicida, Vibrio alginolyticus, and Streptococcus equinus. The growth of A. salmonicida and V. alginolyticus was retarded by red clay, whereas that of S. equinus was promoted. Phase contrast and scanning electron microscopy analyses confirmed the attachment of red clay on cell surfaces, resulting in rapid gravitational removal and cell surface damage in both A. salmonicida and V. alginolyticus, but not in S. equinus. Different cell wall properties of grampositive species may explain the unharmed cell surface of S. equinus. Significant levels of oxidative stress were generated in only the former two species, whereas significant changes in membrane permeability were found only in S. equinus, probably because of its physiological adaptation. The bacterial communities in water samples from Oncorhynchus mykiss aquacultures supplemented with red clay showed similar structure and diversity as those from oxytetracycline-treated water. Taken together, the antibiotic effects of high concentrations of red clay in aquaculture can be attributed to gravitational removal, cell surface damage, and oxidative stress production, and suggest that red clay may be used as an alternative for antibiotics in aquaculture.

  1. Effect of support materials on antibiotic MSW2000 production by immobilized Streptomyces violatus.

    PubMed

    el-Naggar, Mousatfa Y; Hassan, Maha A; Said, Wafa Y Y; el-Aassar, Samy A

    2003-08-01

    The production of an antibiotic by free and immobilized cells of Streptomyces violatus through entrapment or adsorption on different materials was investigated. S. violatus entrapped in Ca-alginate beads gave low antibiotic activity compared to the free cell or adsorbed cell, while the adsorption of S. violatus on sponge cubes yielded the highest antibiotic concentration after 4 days of incubation in static cultures. A starch concentration of 10 g/L was optimum for the production of the antibiotic by adsorbed cells. The weight and size of the sponge cubes used for immobilization influenced production of the antibiotic and the optimum weight and size of the sponge were 0.8 g and 1.0 cm(3), respectively, yielding a maximum antibiotic production of 280 mg/ml. Maximum antibiotic production was obtained at an initial pH value of 7.5 and in an inoculum size of 3 ml (spore suspension) per 50 ml. The production of the antibiotic in a fixed-bed bioreactor reached a maximum value after 2 days of incubation at a circulation rate of 30 ml/h. The immobilized cells in the bioreactor were reused seven successive times over a period of 14 days.

  2. The determinants of the antibiotic resistance process

    PubMed Central

    Franco, Beatriz Espinosa; Altagracia Martínez, Marina; Sánchez Rodríguez, Martha A; Wertheimer, Albert I

    2009-01-01

    Background: The use of antibiotic drugs triggers a complex interaction involving many biological, sociological, and psychological determinants. Resistance to antibiotics is a serious worldwide problem which is increasing and has implications for morbidity, mortality, and health care both in hospitals and in the community. Objectives: To analyze current research on the determinants of antibiotic resistance and comprehensively review the main factors in the process of resistance in order to aid our understanding and assessment of this problem. Methods: We conducted a MedLine search using the key words “determinants”, “antibiotic”, and “antibiotic resistance” to identify publications between 1995 and 2007 on the determinants of antibiotic resistance. Publications that did not address the determinants of antibiotic resistance were excluded. Results: The process and determinants of antibiotic resistance are described, beginning with the development of antibiotics, resistance and the mechanisms of resistance, sociocultural determinants of resistance, the consequences of antibiotic resistance, and alternative measures proposed to combat antibiotic resistance. Conclusions: Analysis of the published literature identified the main determinants of antibiotic resistance as irrational use of antibiotics in humans and animal species, insufficient patient education when antibiotics are prescribed, lack of guidelines for treatment and control of infections, lack of scientific information for physicians on the rational use of antibiotics, and lack of official government policy on the rational use of antibiotics in public and private hospitals. PMID:21694883

  3. Beta-lactam Antibiotics: From Antibiosis to Resistance and Bacteriology

    PubMed Central

    Kong, Kok-Fai; Schneper, Lisa; Mathee, Kalai

    2010-01-01

    SUMMARY This review focuses on the era of antibiosis that led to a better understanding of bacterial morphology, in particlar the cell wall component peptidoglycan. This is an effort to take readers on a tour de force from the concept of antibiosis, to the serepidity of antibiotics, evolution of beta-lactam development, and the molecular biology of antibiotic resistance. These areas of research have culminated in a deeper understanding of microbiology, particularly in the area of bacterial cell wall synthesis and recycling. In spite of this knowledge, which has enabled design of new even more effective therapeutics to combat bacterial infection and has provided new research tools, antibiotic resistance remains a worldwide health care problem. PMID:20041868

  4. Bacterial cytoskeleton and implications for new antibiotic targets.

    PubMed

    Wang, Huan; Xie, Longxiang; Luo, Hongping; Xie, Jianping

    2016-01-01

    Traditionally eukaryotes exclusive cytoskeleton has been found in bacteria and other prokaryotes. FtsZ, MreB and CreS are bacterial counterpart of eukaryotic tubulin, actin filaments and intermediate filaments, respectively. FtsZ can assemble to a Z-ring at the cell division site, regulate bacterial cell division; MreB can form helical structure, and involve in maintaining cell shape, regulating chromosome segregation; CreS, found in Caulobacter crescentus (C. crescentus), can form curve or helical filaments in intracellular membrane. CreS is crucial for cell morphology maintenance. There are also some prokaryotic unique cytoskeleton components playing crucial roles in cell division, chromosome segregation and cell morphology. The cytoskeleton components of Mycobacterium tuberculosis (M. tuberculosis), together with their dynamics during exposure to antibiotics are summarized in this article to provide insights into the unique organization of this formidable pathogen and druggable targets for new antibiotics. PMID:26548775

  5. Antibiotics that target protein synthesis.

    PubMed

    McCoy, Lisa S; Xie, Yun; Tor, Yitzhak

    2011-01-01

    The key role of the bacterial ribosome makes it an important target for antibacterial agents. Indeed, a large number of clinically useful antibiotics target this complex translational ribonucleoprotein machinery. The majority of these compounds, mostly of natural origin, bind to one of the three key ribosomal sites: the decoding (or A-site) on the 30S, the peptidyl transferase center (PTC) on the 50S, and the peptide exit tunnel on the 50S. Antibiotics that bind the A-site, such as the aminoglycosides, interfere with codon recognition and translocation. Peptide bond formation is inhibited when small molecules like oxazolidinones bind at the PTC. Finally, macrolides tend to block the growth of the amino acid chain at the peptide exit tunnel. In this article, the major classes of antibiotics that target the bacterial ribosome are discussed and classified according to their respective target. Notably, most antibiotics solely interact with the RNA components of the bacterial ribosome. The surge seen in the appearance of resistant bacteria has not been met by a parallel development of effective and broad-spectrum new antibiotics, as evident by the introduction of only two novel classes of antibiotics, the oxazolidinones and lipopeptides, in the past decades. Nevertheless, this significant health threat has revitalized the search for new antibacterial agents and novel targets. High resolution structural data of many ribosome-bound antibiotics provide unprecedented insight into their molecular contacts and mode of action and inspire the design and synthesis of new candidate drugs that target this fascinating molecular machine. PMID:21957007

  6. Management Options For Reducing The Release Of Antibiotics And Antibiotic Resistance Genes To The Environment

    EPA Science Inventory

    Background: There is growing concern worldwide about the role of polluted soil and water - 77 environments in the development and dissemination of antibiotic resistance. 78 Objective: To identify management options for reducing the spread of antibiotics and 79 antibiotic resist...

  7. Background antibiotic resistance patterns in antibiotic-free pastured poultry production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antibiotic resistance (AR) is a significant public health issue, and agroecosystems are often viewed as major environmental sources of antibiotic resistant foodborne pathogens. While the use of antibiotics in agroecosystems can potentially increase AR, appropriate background resistance levels in th...

  8. Synergistic interaction of eugenol with antibiotics against Gram negative bacteria.

    PubMed

    Hemaiswarya, S; Doble, M

    2009-11-01

    Eugenol, the principal chemical component of clove oil from Eugenia aromatica has been long known for its analgesic, local anesthetic, anti-inflammatory, and antibacterial effects. The interaction of the eugenol with ten different hydrophobic and hydrophilic antibiotics was studied against five different Gram negative bacteria. The MIC of the combination was found to decrease by a factor of 5-1000 with respect to their individual MIC. This synergy is because of the membrane damaging nature of eugenol, where 1mM of its concentration is able to damage nearly 50% of the bacterial membrane. Eugenol was also able to enhance the activities of lysozyme, Triton X-100 and SDS in damaging the bacterial cell membrane. The hydrophilic antibiotics such as vancomycin and beta-lactam antibiotics which have a marginal activity on these gram negative bacteria exhibit an enhanced antibacterial activity when pretreated with eugenol. Reduced usage of antibiotics could be employed as a treatment strategy to slow down the onset of antibiotic resistance as well as decrease its toxicity. Experiments performed with human blood cells indicated that the concentration of eugenol used for the combination studies were below its cytotoxic values. Pharmacodynamic studies of the combinations need to be performed to decide on the effective dosage. PMID:19540744

  9. Electro-Fenton degradation of the antibiotic sulfanilamide with Pt/carbon-felt and BDD/carbon-felt cells. Kinetics, reaction intermediates, and toxicity assessment.

    PubMed

    El-Ghenymy, Abdellatif; Rodríguez, Rosa María; Brillas, Enric; Oturan, Nihal; Oturan, Mehmet A

    2014-01-01

    The degradation of 230 mL of a 0.6-mM sulfanilamide solution in 0.05 M Na₂SO₄ of pH 3.0 has been studied by electro-Fenton process. The electrolytic cell contained either a Pt or boron-doped diamond (BDD) anode and a carbon-felt cathode. Under these conditions, organics are oxidized by hydroxyl radicals formed at the anode surface from water oxidation and in the bulk from Fenton's reaction between initially added (and then electrochemically regenerated) Fe(2+) and cathodically generated H₂O₂. From the decay of sulfanilamide concentration determined by reversed-phase liquid chromatography, an optimum Fe(2+) concentration of 0.20 mM in both cells was found. The drug disappeared more rapidly using BDD than Pt, and, in both cases, it was more quickly removed with raising applied current. Almost total mineralization was achieved using the BDD/carbon-felt cell, whereas the alternative use of Pt anode led to a slightly lower mineralization degree. In both cells, the degradation rate was accelerated at higher current but with the concomitant fall of mineralization current efficiency due to the greater increase in rate of the parasitic reactions of hydroxyl radicals. Reversed-phase liquid chromatography allowed the identification of catechol, resorcinol, hydroquinone, p-benzoquinone, and 1,2,4-trihydroxybenzene as aromatic intermediates, whereas ion exclusion chromatography revealed the formation of malic, maleic, fumaric, acetic, oxalic, formic, and oxamic acids. NH₄(+), NO₃(-), and SO₄(2-) ions were released during the electro-Fenton process. A plausible reaction sequence for sulfanilamide mineralization involving all detected intermediates has been proposed. The toxicity of the solution was assessed from the Vibrio fischeri bacteria luminescence inhibition. Although it acquired its maximum value at short electrolysis time, the solution was completely detoxified at the end of the electro-Fenton treatment, regardless of the anode used. PMID:24687785

  10. A New Approach for the Discovery of Antibiotics by Targeting Non-Multiplying Bacteria: A Novel Topical Antibiotic for Staphylococcal Infections

    PubMed Central

    Hu, Yanmin; Shamaei-Tousi, Alireza; Liu, Yingjun; Coates, Anthony

    2010-01-01

    In a clinical infection, multiplying and non-multiplying bacteria co-exist. Antibiotics kill multiplying bacteria, but they are very inefficient at killing non-multipliers which leads to slow or partial death of the total target population of microbes in an infected tissue. This prolongs the duration of therapy, increases the emergence of resistance and so contributes to the short life span of antibiotics after they reach the market. Targeting non-multiplying bacteria from the onset of an antibiotic development program is a new concept. This paper describes the proof of principle for this concept, which has resulted in the development of the first antibiotic using this approach. The antibiotic, called HT61, is a small quinolone-derived compound with a molecular mass of about 400 Daltons, and is active against non-multiplying bacteria, including methicillin sensitive and resistant, as well as Panton-Valentine leukocidin-carrying Staphylococcus aureus. It also kills mupirocin resistant MRSA. The mechanism of action of the drug is depolarisation of the cell membrane and destruction of the cell wall. The speed of kill is within two hours. In comparison to the conventional antibiotics, HT61 kills non-multiplying cells more effectively, 6 logs versus less than one log for major marketed antibiotics. HT61 kills methicillin sensitive and resistant S. aureus in the murine skin bacterial colonization and infection models. No resistant phenotype was produced during 50 serial cultures over a one year period. The antibiotic caused no adverse affects after application to the skin of minipigs. Targeting non-multiplying bacteria using this method should be able to yield many new classes of antibiotic. These antibiotics may be able to reduce the rate of emergence of resistance, shorten the duration of therapy, and reduce relapse rates. PMID:20676403

  11. Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs)

    PubMed Central

    Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B.; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E.; Sotgia, Federica; Lisanti, Michael P.

    2016-01-01

    Bedaquiline (a.k.a., Sirturo) is an anti-microbial agent, which is approved by the FDA for the treatment of multi-drug resistant pulmonary tuberculosis (TB). Bedaquiline is a first-in-class diaryl-quinoline compound, that mechanistically inhibits the bacterial ATP-synthase, and shows potent activity against both drug-sensitive and drug-resistant TB. Interestingly, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. Thus, we hypothesized that, in mammalian cells, bedaquiline might also target the mitochondrial ATP-synthase, leading to mitochondrial dysfunction and ATP depletion. Here, we show that bedaquiline has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that bedaquiline treatment of MCF7 breast cancer cells inhibits mitochondrial oxygen-consumption, as well as glycolysis, but induces oxidative stress. Importantly, bedaquiline significantly blocks the propagation and expansion of MCF7-derived CSCs, with an IC-50 of approx. 1-μM, as determined using the mammosphere assay. Similarly, bedaquiline also reduces both the CD44+/CD24low/− CSC and ALDH+ CSC populations, under anchorage-independent growth conditions. In striking contrast, bedaquiline significantly increases oxygen consumption in normal human fibroblasts, consistent with the fact that it is well-tolerated in patients treated for TB infections. As such, future pre-clinical studies and human clinical trials in cancer patients may be warranted. Interestingly, we also highlight that bedaquiline shares certain structural similarities with trans-piceatannol and trans-resveratrol, which are known natural flavonoid inhibitors of the mitochondrial ATP-synthase (complex V) and show anti-aging properties. PMID:27344270

  12. Bedaquiline, an FDA-approved antibiotic, inhibits mitochondrial function and potently blocks the proliferative expansion of stem-like cancer cells (CSCs).

    PubMed

    Fiorillo, Marco; Lamb, Rebecca; Tanowitz, Herbert B; Cappello, Anna Rita; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2016-08-01

    Bedaquiline (a.k.a., Sirturo) is an anti-microbial agent, which is approved by the FDA for the treatment of multi-drug resistant pulmonary tuberculosis (TB). Bedaquiline is a first-in-class diaryl-quinoline compound, that mechanistically inhibits the bacterial ATP-synthase, and shows potent activity against both drug-sensitive and drug-resistant TB. Interestingly, eukaryotic mitochondria originally evolved from engulfed aerobic bacteria. Thus, we hypothesized that, in mammalian cells, bedaquiline might also target the mitochondrial ATP-synthase, leading to mitochondrial dysfunction and ATP depletion. Here, we show that bedaquiline has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that bedaquiline treatment of MCF7 breast cancer cells inhibits mitochondrial oxygen-consumption, as well as glycolysis, but induces oxidative stress. Importantly, bedaquiline significantly blocks the propagation and expansion of MCF7-derived CSCs, with an IC-50 of approx. 1-μM, as determined using the mammosphere assay. Similarly, bedaquiline also reduces both the CD44+/CD24low/- CSC and ALDH+ CSC populations, under anchorage-independent growth conditions. In striking contrast, bedaquiline significantly increases oxygen consumption in normal human fibroblasts, consistent with the fact that it is well-tolerated in patients treated for TB infections. As such, future pre-clinical studies and human clinical trials in cancer patients may be warranted. Interestingly, we also highlight that bedaquiline shares certain structural similarities with trans-piceatannol and trans-resveratrol, which are known natural flavonoid inhibitors of the mitochondrial ATP-synthase (complex V) and show anti-aging properties. PMID:27344270

  13. [Alliance against MDRO: safeguarding antibiotics].

    PubMed

    Carlet, J; Rambaud, C; Pulcini, C

    2012-09-01

    Resistance to antibiotics has increased recently to a dramatic extend, and the pipeline of new antibiotics is almost dry for the 5 next years. Failures happen already for trivial community acquired infections, like pyelonephritis, or peritonitis, and this is likely to increase. Difficult surgical procedures, transplants, and other immunosuppressive therapies will become far more risky. Resistance is mainly due to an excessive usage of antibiotics, in all sectors, including the animal one. Action is urgently needed. Therefore, an alliance against MDRO has been recently created, which includes health care professionals, consumers, health managers, and politicians. The document highlights the different proposed measures, and represents a strong consensus between the different professionals, including general practitioners, and veterinarians.

  14. Nucleoside antibiotics: biosynthesis, regulation, and biotechnology.

    PubMed

    Niu, Guoqing; Tan, Huarong

    2015-02-01

    The alarming rise in antibiotic-resistant pathogens has coincided with a decline in the supply of new antibiotics. It is therefore of great importance to find and create new antibiotics. Nucleoside antibiotics are a large family of natural products with diverse biological functions. Their biosynthesis is a complex process through multistep enzymatic reactions and is subject to hierarchical regulation. Genetic and biochemical studies of the biosynthetic machinery have provided the basis for pathway engineering and combinatorial biosynthesis to create new or hybrid nucleoside antibiotics. Dissection of regulatory mechanisms is leading to strategies to increase the titer of bioactive nucleoside antibiotics.

  15. Applications of Local Antibiotics in Orthopedic Trauma.

    PubMed

    Cancienne, Jourdan M; Burrus, M Tyrrell; Weiss, David B; Yarboro, Seth R

    2015-10-01

    Local antibiotics have a role in orthopedic trauma for both infection prophylaxis and treatment. They provide the advantage of high local antibiotic concentration without excessive systemic levels. Nonabsorbable polymethylmethacrylate (PMMA) is a popular antibiotic carrier, but absorbable options including bone graft, bone graft substitutes, and polymers have gained acceptance. Simple aqueous antibiotic solutions continue to be investigated and appear to be clinically effective. For established infections, such as osteomyelitis, a combination of surgical debridement with local and systemic antibiotics seems to represent the most effective treatment at this time. Further investigation of more effective local antibiotic utilization is ongoing.

  16. Helping Chemists Discover New Antibiotics.

    PubMed

    Blaskovich, Mark A T; Zuegg, Johannes; Elliott, Alysha G; Cooper, Matthew A

    2015-07-10

    The world is facing a crisis in treating infectious diseases, with a scarcity of new antibiotics in development to treat the growing threat of drug-resistant "superbugs". We need new strategies to reinvigorate the antibiotic pipeline. In this Viewpoint we discuss one such approach, encouraging the community of synthetic chemists to participate in testing chemical diversity from their laboratories for antimicrobial potential. CO-ADD, the Community for Open Antimicrobial Drug Discovery, offers free screening against five bacteria and two fungi with follow up hit confirmation and validation, all with no strings attached. PMID:27622818

  17. [Mercurimetric determination of cephalosporin antibiotics].

    PubMed

    Pospísilová, B; Kubes, J

    1988-04-01

    The conditions for a potenciometric estimation of cefuroxime, cefsulodin, cefotaxime and ceftriaxon with mercury(II) perchlorate after the previous reaction of the antibiotics with hydroxylamine were established. The mercurimetric determination was well reproducible with the relative error of the mean ranging up to 1% and the results are identical with the spectrometric and microbiological determination. There is no need to use a standard. With this technique only the content of effective antibiotic with an intact beta-lactam ring can be estimated. The method did not provide objective results for cefoperazone and cefoxitin. The direct determination of cephalosporin degradation products was verified for cefalexin, cefalothin, cefuroxime, cefsulodin and ceftriaxon.

  18. Cefuroxime - a new cephalosporin antibiotic.

    PubMed

    O'Callaghan, C H; Sykes, R B; Ryan, D M; Foord, R D; Muggleton, P W

    1976-01-01

    Cefuroxime is a new broad spectrum cephalosporin antibiotic for administration by injection. It is stable to most beta-lactamases. It is active against gram-positive organisms, including penicillinase-producing staphylococci, and has wide activity against gram-negative bacilli including Enterobacter and many strains of indole-positive Proteus spp. The substance is also highly active against Haemophilus influenzae and Neisseria gonorrhoeae. Studies on human volunteers showed that it produced high, long-lasting blood levels with virtually complete recovery of unchanged antibiotic in the urine. No evidence of toxicity due to cefuroxime was found. Slight, short-lived pain followed intramuscular injection, and the compound was well tolerated intravenously.

  19. Current status of antibiotic resistance in animal production.

    PubMed

    Franklin, A

    1999-01-01

    It is generally accepted that the more antibiotics we use, the faster bacteria will develop resistance. Further it has been more or less accepted that once an antibiotic is withdrawn from the clinic, the resistance genes will eventually disappear, [table: see text] since they will no more be of any survival value for the bacterial cell. However, recent research has shown that after a long time period of exposure to antibiotics, certain bacterial species may adapt to this environment in such a way that they keep their resistance genes stably also after the removal of antibiotics. Thus, there is reason to believe that once resistance has developed it will not even in the long term be eradicated. What then can we do not to increase further the already high level of antibiotic-resistant bacteria in animals? We should of course encourage a prudent use of these valuable drugs. In Sweden antibiotics are not used for growth promoting purposes and are available only after veterinary prescription on strict indications. Generally, antimicrobial treatment of animals on individual or on herd basis should not be considered unless in connection with relevant diagnostics. The amounts of antibiotics used and the development of resistance in important pathogens should be closely monitored. Furthermore, resistance monitoring in certain non-pathogenic intestinal bacteria, which may serve as a reservoir for resistance genes is probably more important than hitherto anticipated. Once the usage of or resistance to a certain antibiotic seems to increase in an alarming way, steps should be taken to limit the usage of the drug in order to prevent further spread of resistance genes in animals, humans and the environment. Better methods for detecting and quantifying antibiotic resistance have to be developed. Screening methods must be standardized and evaluated in order to obtain comparable and reliable results from different countries. The genetic mechanisms for development of resistance and

  20. Antibiotic treatment selects for cooperative virulence of Salmonella typhimurium.

    PubMed

    Diard, Médéric; Sellin, Mikael E; Dolowschiak, Tamas; Arnoldini, Markus; Ackermann, Martin; Hardt, Wolf-Dietrich

    2014-09-01

    Antibiotics are powerful therapeutics but are not equally effective against all cells in bacterial populations. Bacteria that express an antibiotic-tolerant phenotype ("persisters") can evade treatment [1]. Persisters can cause relapses of the infection after the end of the therapy [2]. It is still poorly understood whether persistence affects the evolution of bacterial virulence. During infections, persisters have been found preferentially at particular sites within the host [3, 4]. If bacterial virulence factors are required to reach such sites, treatment with antibiotics could impose selection on the expression of virulence genes, in addition to their well-established effects on bacterial resistance. Here, we report that treatment with antibiotics selects for virulence and fosters transmissibility of Salmonella Typhimurium. In a mouse model for Salmonella diarrhea, treatment with the broad-spectrum antibiotic ciprofloxacin reverses the outcome of competition between wild-type bacteria and avirulent mutants that can spontaneously arise during within-host evolution [5]. While avirulent mutants take over the gut lumen and abolish disease transmission in untreated mice, ciprofloxacin tilts the balance in favor of virulent, wild-type bacteria. This is explained by the need for virulence factors to invade gut tissues and form a persistent reservoir. Avirulent mutants remain in the gut lumen and are eradicated. Upon cessation of antibiotic treatment, tissue-lodged wild-type pathogens reseed the gut lumen and thereby facilitate disease transmissibility to new hosts. Our results suggest a general principle by which antibiotic treatment can promote cooperative virulence during within-host evolution, increase duration of transmissibility, and thereby enhance the spread of an infectious disease. PMID:25131673

  1. Antibiotic treatment selects for cooperative virulence of Salmonella typhimurium.

    PubMed

    Diard, Médéric; Sellin, Mikael E; Dolowschiak, Tamas; Arnoldini, Markus; Ackermann, Martin; Hardt, Wolf-Dietrich

    2014-09-01

    Antibiotics are powerful therapeutics but are not equally effective against all cells in bacterial populations. Bacteria that express an antibiotic-tolerant phenotype ("persisters") can evade treatment [1]. Persisters can cause relapses of the infection after the end of the therapy [2]. It is still poorly understood whether persistence affects the evolution of bacterial virulence. During infections, persisters have been found preferentially at particular sites within the host [3, 4]. If bacterial virulence factors are required to reach such sites, treatment with antibiotics could impose selection on the expression of virulence genes, in addition to their well-established effects on bacterial resistance. Here, we report that treatment with antibiotics selects for virulence and fosters transmissibility of Salmonella Typhimurium. In a mouse model for Salmonella diarrhea, treatment with the broad-spectrum antibiotic ciprofloxacin reverses the outcome of competition between wild-type bacteria and avirulent mutants that can spontaneously arise during within-host evolution [5]. While avirulent mutants take over the gut lumen and abolish disease transmission in untreated mice, ciprofloxacin tilts the balance in favor of virulent, wild-type bacteria. This is explained by the need for virulence factors to invade gut tissues and form a persistent reservoir. Avirulent mutants remain in the gut lumen and are eradicated. Upon cessation of antibiotic treatment, tissue-lodged wild-type pathogens reseed the gut lumen and thereby facilitate disease transmissibility to new hosts. Our results suggest a general principle by which antibiotic treatment can promote cooperative virulence during within-host evolution, increase duration of transmissibility, and thereby enhance the spread of an infectious disease.

  2. Probiotic approach to prevent antibiotic resistance.

    PubMed

    Ouwehand, Arthur C; Forssten, Sofia; Hibberd, Ashley A; Lyra, Anna; Stahl, Buffy

    2016-01-01

    Probiotics are live microorganisms, mainly belonging to the genera Lactobacillus and Bifidobacterium, although also strain of other species are commercialized, that have a beneficial effect on the host. From the perspective of antibiotic use, probiotics have been observed to reduce the risk of certain infectious disease such as certain types of diarrhea and respiratory tract infection. This may be accompanied with a reduced need of antibiotics for secondary infections. Antibiotics tend to be effective against most common diseases, but increasingly resistance is being observed among pathogens. Probiotics are specifically selected to not contribute to the spread of antibiotic resistance and not carry transferable antibiotic resistance. Concomitant use of probiotics with antibiotics has been observed to reduce the incidence, duration and/or severity of antibiotic-associated diarrhea. This contributes to better adherence to the antibiotic prescription and thereby reduces the evolution of resistance. To what extent probiotics directly reduce the spread of antibiotic resistance is still much under investigation; but maintaining a balanced microbiota during antibiotic use may certainly provide opportunities for reducing the spread of resistances. Key messages Probiotics may reduce the risk for certain infectious diseases and thereby reduce the need for antibiotics. Probiotics may reduce the risk for antibiotic-associated diarrhea Probiotics do not contribute to the spread of antibiotic resistance and may even reduce it.

  3. Synergistic Photothermal and Antibiotic Killing of Biofilm-Associated Staphylococcus aureus Using Targeted Antibiotic-Loaded Gold Nanoconstructs

    PubMed Central

    2016-01-01

    Resistance to conventional antibiotics is a growing public health concern that is quickly outpacing the development of new antibiotics. This has led the Infectious Diseases Society of America (IDSA) to designate Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species as “ESKAPE pathogens” on the basis of the rapidly decreasing availability of useful antibiotics. This emphasizes the urgent need for alternative therapeutic strategies to combat infections caused by these and other bacterial pathogens. In this study, we used Staphylococcus aureus (S. aureus) as a proof-of-principle ESKAPE pathogen to demonstrate that an appropriate antibiotic (daptomycin) can be incorporated into polydopamine-coated gold nanocages (AuNC@PDA) and that daptomycin-loaded AuNC@PDA can be conjugated to antibodies targeting a species-specific surface protein (staphylococcal protein A; Spa) as a means of achieving selective delivery of the nanoconstructs directly to the bacterial cell surface. Targeting specificity was confirmed by demonstrating a lack of binding to mammalian cells, reduced photothermal and antibiotic killing of the Spa-negative species Staphylococcus epidermidis, and reduced killing of S. aureus in the presence of unconjugated anti-Spa antibodies. We demonstrate that laser irradiation at levels within the current safety standard for use in humans can be used to achieve both a lethal photothermal effect and controlled release of the antibiotic, thus resulting in a degree of therapeutic synergy capable of eradicating viable S. aureus cells. The system was validated using planktonic bacterial cultures of both methicillin-sensitive and methicillin-resistant S. aureus strains and subsequently shown to be effective in the context of an established biofilm, thus indicating that this approach could be used to facilitate the effective treatment of intrinsically resistant biofilm infections. PMID

  4. Correlative Time-Resolved Fluorescence Microscopy To Assess Antibiotic Diffusion-Reaction in Biofilms

    PubMed Central

    Daddi Oubekka, S.; Briandet, R.; Fontaine-Aupart, M.-P.

    2012-01-01

    The failure of antibiotics to inactivate in vivo pathogens organized in biofilms has been shown to trigger chronic infections. In addition to mechanisms involving specific genetic or physiological cell properties, antibiotic sorption and/or reaction with biofilm components may lessen the antibiotic bioavailability and consequently decrease their efficiency. To assess locally and accurately the antibiotic diffusion-reaction, we used for the first time a set of advanced fluorescence microscopic tools (fluorescence recovery after photobleaching, fluorescence correlation spectroscopy, and fluorescence lifetime imaging) that offer a spatiotemporal resolution not available with the commonly used time-lapse confocal imaging method. This set of techniques was used to characterize the dynamics of fluorescently labeled vancomycin in biofilms formed by two Staphylococcus aureus human isolates. We demonstrate that, at therapeutic concentrations of vancomycin, the biofilm matrix was not an obstacle to the diffusion-reaction of the antibiotic that can reach all cells through the biostructure. PMID:22450986

  5. Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.

    PubMed

    Kubicek-Sutherland, Jessica Z; Heithoff, Douglas M; Ersoy, Selvi C; Shimp, William R; House, John K; Marth, Jamey D; Smith, Jeffrey W; Mahan, Michael J

    2015-09-01

    Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

  6. Mycobacteriophage putative GTPase-activating protein can potentiate antibiotics.

    PubMed

    Yan, Shuangquan; Xu, Mengmeng; Duan, Xiangke; Yu, Zhaoxiao; Li, Qiming; Xie, Longxiang; Fan, Xiangyu; Xie, Jianping

    2016-09-01

    The soaring incidences of infection by antimicrobial resistant (AR) pathogens and shortage of effective antibiotics with new mechanisms of action have renewed interest in phage therapy. This scenario is exemplified by resistant tuberculosis (TB), caused by resistant Mycobacterium tuberculosis. Mycobacteriophage SWU1 A321_gp67 encodes a putative GTPase-activating protein. Mycobacterium smegmatis with gp67 overexpression showed changed colony formation and biofilm morphology and supports the efficacy of streptomycin and capreomycin against Mycobacterium. gp67 down-regulated the transcription of genes involved in cell wall and biofilm development. To our knowledge, this is the first report to show that phage protein in addition to lysin or recombination components can synergize with existing antibiotics. Phage components might represent a promising new clue for better antibiotic potentiators. PMID:27345061

  7. Antibodies: an alternative for antibiotics?

    PubMed

    Berghman, L R; Abi-Ghanem, D; Waghela, S D; Ricke, S C

    2005-04-01

    In 1967, the success of vaccination programs, combined with the seemingly unstoppable triumph of antibiotics, prompted the US Surgeon General to declare that "it was time to close the books on infectious diseases." We now know that the prediction was overly optimistic and that the fight against infectious diseases is here to stay. During the last 20 yr, infectious diseases have indeed made a staggering comeback for a variety of reasons, including resistance against existing antibiotics. As a consequence, several alternatives to antibiotics are currently being considered or reconsidered. Passive immunization (i.e., the administration of more or less pathogen-specific antibodies to the patient) prior to or after exposure to the disease-causing agent is one of those alternative strategies that was almost entirely abandoned with the introduction of chemical antibiotics but that is now gaining interest again. This review will discuss the early successes and limitations of passive immunization, formerly referred to as "serum therapy," the current use of antibody administration for prophylaxis or treatment of infectious diseases in agriculture, and, finally, recent developments in the field of antibody engineering and "molecular farming" of antibodies in various expression systems. Especially the potential of producing therapeutic antibodies in crops that are routine dietary components of farm animals, such as corn and soy beans, seems to hold promise for future application in the fight against infectious diseases. PMID:15844826

  8. Antibiotics and the burn patient.

    PubMed

    Ravat, François; Le-Floch, Ronan; Vinsonneau, Christophe; Ainaud, Pierre; Bertin-Maghit, Marc; Carsin, Hervé; Perro, Gérard

    2011-02-01

    Infection is a major problem in burn care and especially when it is due to bacteria with hospital-acquired multi-resistance to antibiotics. Moreover, when these bacteria are Gram-negative organisms, the most effective molecules are 20 years old and there is little hope of any new product available even in the distant future. Therefore, it is obvious that currently available antibiotics should not be misused. With this aim in mind, the following review was conducted by a group of experts from the French Society for Burn Injuries (SFETB). It examined key points addressing the management of antibiotics for burn patients: when to use or not, time of onset, bactericidia, combination, adaptation, de-escalation, treatment duration and regimen based on pharmacokinetic and pharmacodynamic characteristics of these compounds. The authors also considered antibioprophylaxis and some other key points such as: infection diagnosis criteria, bacterial inoculae and local treatment. French guidelines for the use of antibiotics in burn patients have been designed up from this work.

  9. Antibiotics and the burn patient.

    PubMed

    Ravat, François; Le-Floch, Ronan; Vinsonneau, Christophe; Ainaud, Pierre; Bertin-Maghit, Marc; Carsin, Hervé; Perro, Gérard

    2011-02-01

    Infection is a major problem in burn care and especially when it is due to bacteria with hospital-acquired multi-resistance to antibiotics. Moreover, when these bacteria are Gram-negative organisms, the most effective molecules are 20 years old and there is little hope of any new product available even in the distant future. Therefore, it is obvious that currently available antibiotics should not be misused. With this aim in mind, the following review was conducted by a group of experts from the French Society for Burn Injuries (SFETB). It examined key points addressing the management of antibiotics for burn patients: when to use or not, time of onset, bactericidia, combination, adaptation, de-escalation, treatment duration and regimen based on pharmacokinetic and pharmacodynamic characteristics of these compounds. The authors also considered antibioprophylaxis and some other key points such as: infection diagnosis criteria, bacterial inoculae and local treatment. French guidelines for the use of antibiotics in burn patients have been designed up from this work. PMID:20510518

  10. Antibiotic resistance in probiotic bacteria

    PubMed Central

    Gueimonde, Miguel; Sánchez, Borja; G. de los Reyes-Gavilán, Clara; Margolles, Abelardo

    2013-01-01

    Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. The main probiotic bacteria are strains belonging to the genera Lactobacillus and Bifidobacterium, although other representatives, such as Bacillus or Escherichia coli strains, have also been used. Lactobacillus and Bifidobacterium are two common inhabitants of the human intestinal microbiota. Also, some species are used in food fermentation processes as starters, or as adjunct cultures in the food industry. With some exceptions, antibiotic resistance in these beneficial microbes does not constitute a safety concern in itself, when mutations or intrinsic resistance mechanisms are responsible for the resistance phenotype. In fact, some probiotic strains with intrinsic antibiotic resistance could be useful for restoring the gut microbiota after antibiotic treatment. However, specific antibiotic resistance determinants carried on mobile genetic elements, such as tetracycline resistance genes, are often detected in the typical probiotic genera, and constitute a reservoir of resistance for potential food or gut pathogens, thus representing a serious safety issue. PMID:23882264

  11. Spatial mapping of antibiotic resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A serious concern for modern animal production is the fear that feed antimicrobials, such as monensin, increase the potential for high levels of antibiotic resistant (AR) gene prevalence in the manure, which may subsequently be shared with soil communities and eventually be taken up by human pathoge...

  12. Gunacin, a new quinone antibiotic from Ustilago sp.

    PubMed

    Werner, R G; Appel, K R; Merk, W M

    1979-11-01

    In a screening program for antibiotics which were antagonized by cysteine, a strain, which was characterized as Ustilago sp., was found to produce a new quinone antibiotic, gunacin. The molecular weight M+ = 348.084 determined by mass spectroscopy, corresponds to a molecular formula of C17H16O8. Further spectroscopic data prove that gunacin is a new antibiotic. The antibiotic possesses a good inhibitory effect against mycoplasmas and Gram-positive bacteria including multi-resistant strains. It also possesses a weak activity against Gram-negative bacteria with the exception of Proteus vulgaris, which is more strongly inhibited. The main activity against fungi is found against Trichophyton mentagrophytes. Gunacin shows an inhibition of the DNA synthesis in vivo, is antagonized by mercapto compounds and possesses an acute toxicity of LD50 = 16 mg/kg i.p. and LD50 = 12 mg/kg i.v. in mice. Against HeLa-cell the antibiotic shows an ED50 = 12.11 microgram/ml. Thirty five microgram/ml of gunacin induces 1,063 interferon units. PMID:528380

  13. The ABC of Ribosome-Related Antibiotic Resistance.

    PubMed

    Wilson, Daniel N

    2016-01-01

    The increase in multidrug-resistant pathogenic bacteria is limiting the utility of our current arsenal of antimicrobial agents. Mechanistically understanding how bacteria obtain antibiotic resistance is a critical first step to the development of improved inhibitors. One common mechanism for bacteria to obtain antibiotic resistance is by employing ATP-binding cassette (ABC) transporters to actively pump the drug from the cell. The ABC-F family includes proteins conferring resistance to a variety of clinically important ribosome-targeting antibiotics; however, controversy remains as to whether resistance is conferred via efflux like other ABC transporters or whether another mechanism, such as ribosome protection, is at play. A recent study by Sharkey and coworkers (L. K. Sharkey, T. A. Edwards, and A. J. O'Neill, mBio 7:e01975-15, 2016, http://dx.doi.org/10.1128/mBio.01975-15) provides strong evidence that ABC-F proteins conferring antibiotic resistance utilize ribosome protection mechanisms, namely, by interacting with the ribosome and displacing the drug from its binding site, thus revealing a novel role for ABC-F proteins in antibiotic resistance. PMID:27143393

  14. Method of evaluating effects of antibiotics on bacterial biofilm.

    PubMed Central

    Prosser, B L; Taylor, D; Dix, B A; Cleeland, R

    1987-01-01

    Antibiotics are generally not effective against organisms in exopolysaccharide biofilms. A simple method of studying the effect of antibiotics on bacteria in established biofilms is reported. Escherichia coli ATCC 25922 cells grown overnight at 37 degrees C on Mueller-Hinton agar were suspended in buffer and dispensed on 0.5-cm2 catheter disks. The disks were incubated for 1 h at 37 degrees C, washed, transferred to petri dishes containing 20 ml of broth, and incubated at 37 degrees C for 20 to 22 h, at which time thick biofilms were established. Disks were washed, placed in broth or broth containing antibiotic, and incubated at 37 degrees C for 4 h. The disks were removed, and viable counts were determined. This process was repeated at other selected time intervals (e.g., 8 and 24 h). Viable bacterial counts decreased from 10(3) to 10(4) CFU/cm2 in 24 h with 400 micrograms of amdinocillin or cefamandole per ml. A combination containing 400 micrograms of each antibiotic per ml decreased the viable counts to an undetectable level (less than 100 CFU/cm2) in 24 h. Other antibiotics and organisms were also examined in this system. Images PMID:3435100

  15. The ABC of Ribosome-Related Antibiotic Resistance.

    PubMed

    Wilson, Daniel N

    2016-05-03

    The increase in multidrug-resistant pathogenic bacteria is limiting the utility of our current arsenal of antimicrobial agents. Mechanistically understanding how bacteria obtain antibiotic resistance is a critical first step to the development of improved inhibitors. One common mechanism for bacteria to obtain antibiotic resistance is by employing ATP-binding cassette (ABC) transporters to actively pump the drug from the cell. The ABC-F family includes proteins conferring resistance to a variety of clinically important ribosome-targeting antibiotics; however, controversy remains as to whether resistance is conferred via efflux like other ABC transporters or whether another mechanism, such as ribosome protection, is at play. A recent study by Sharkey and coworkers (L. K. Sharkey, T. A. Edwards, and A. J. O'Neill, mBio 7:e01975-15, 2016, http://dx.doi.org/10.1128/mBio.01975-15) provides strong evidence that ABC-F proteins conferring antibiotic resistance utilize ribosome protection mechanisms, namely, by interacting with the ribosome and displacing the drug from its binding site, thus revealing a novel role for ABC-F proteins in antibiotic resistance.

  16. Antibiotics May Blunt Breast-Feeding's Benefits

    MedlinePlus

    ... how it helps a baby develop intestinal bacteria (microbiota), and that antibiotics disturb that development, she said. ... the mother guides the development of the infant's microbiota," she said. "Antibiotic use disrupts the natural microbiota ...

  17. Origins and Evolution of Antibiotic Resistance

    PubMed Central

    Davies, Julian; Davies, Dorothy

    2010-01-01

    Summary: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory. PMID:20805405

  18. Antibiotics Overprescribed for Possible STDs: Study

    MedlinePlus

    ... There is a tricky balance between not furthering antibiotic resistance by over-prescribing, but also still getting people ... a national and international priority to help prevent antibiotic resistance, which would threaten our ability to treat even ...

  19. Alliance for the Prudent Use of Antibiotics

    MedlinePlus

    ... Competencies Current Projects Completed Projects The Center for Adaptation Genetics and Drug Resistance Reservoirs of Antibiotic Resistance ... visit our partner lab at the Center for Adaptation Genetics and Drug Resistance . Antibiotic Resistance in the ...

  20. When and How to Take Antibiotics

    MedlinePlus

    ... Work Contact Us ABOUT THE ISSUE What is Antibiotic Resistance? General Background Science of Resistance Glossary References POLICY ... for Adaptation Genetics and Drug Resistance Reservoirs of Antibiotic Resistance Project (ROAR) INTERNATIONAL CHAPTERS APUA Chapter Network Africa ...

  1. Antibiotic stewardship programmes and the surgeon's role.

    PubMed

    Çakmakçi, M

    2015-04-01

    Inappropriate antibiotic use is a frequent occurrence, especially in surgical units. Among the unnecessary costs of such usage are unfavourable outcomes for patients and the emergence and spread of resistant bacteria. Antibiotic stewardship programmes aim to limit the spread of antibiotic resistance by promoting thoughtful prescribing of antibiotics. Such programmes usually try to control inappropriate use of antibiotics; to optimize the choice of drug, dosing, route, and duration of therapy; to maximize clinical cure or prevention of infection; and to limit unwanted effects and excess cost. In this paper, I discuss the impact of improper use of antibiotics and outline why I believe that antibiotic stewardship is likely to be the best way of dealing with it. Engagement of surgeons in antibiotic stewardship programmes is crucial to their success.

  2. FDA Bolsters Warnings about Class of Antibiotics

    MedlinePlus

    ... 160078.html FDA Bolsters Warnings About Class of Antibiotics Fluoroquinolones such as Cipro, Levaquin should be reserved ... it's strengthening label warnings on a class of antibiotics called fluoroquinolones because the drugs can lead to ...

  3. Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy

    PubMed Central

    Wong, Michael; Daly, Seth M.; Greenberg, David E.; Toprak, Erdal

    2016-01-01

    The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene’s sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities. PMID:27631336

  4. Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy.

    PubMed

    Ayhan, Dilay Hazal; Tamer, Yusuf Talha; Akbar, Mohammed; Bailey, Stacey M; Wong, Michael; Daly, Seth M; Greenberg, David E; Toprak, Erdal

    2016-09-01

    The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene's sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities. PMID:27631336

  5. Sequence-Specific Targeting of Bacterial Resistance Genes Increases Antibiotic Efficacy.

    PubMed

    Ayhan, Dilay Hazal; Tamer, Yusuf Talha; Akbar, Mohammed; Bailey, Stacey M; Wong, Michael; Daly, Seth M; Greenberg, David E; Toprak, Erdal

    2016-09-01

    The lack of effective and well-tolerated therapies against antibiotic-resistant bacteria is a global public health problem leading to prolonged treatment and increased mortality. To improve the efficacy of existing antibiotic compounds, we introduce a new method for strategically inducing antibiotic hypersensitivity in pathogenic bacteria. Following the systematic verification that the AcrAB-TolC efflux system is one of the major determinants of the intrinsic antibiotic resistance levels in Escherichia coli, we have developed a short antisense oligomer designed to inhibit the expression of acrA and increase antibiotic susceptibility in E. coli. By employing this strategy, we can inhibit E. coli growth using 2- to 40-fold lower antibiotic doses, depending on the antibiotic compound utilized. The sensitizing effect of the antisense oligomer is highly specific to the targeted gene's sequence, which is conserved in several bacterial genera, and the oligomer does not have any detectable toxicity against human cells. Finally, we demonstrate that antisense oligomers improve the efficacy of antibiotic combinations, allowing the combined use of even antagonistic antibiotic pairs that are typically not favored due to their reduced activities.

  6. The In vitro Antibiotic Tolerant Persister Population in Burkholderia pseudomallei is Altered by Environmental Factors

    PubMed Central

    Nierman, William C.; Yu, Yan; Losada, Liliana

    2015-01-01

    Bacterial persistence due to antibiotic tolerance is a critical aspect of antibiotic treatment failure, disease latency, and chronic or reemergent infections. The levels of persisters is especially notable for the opportunistic Gram-negative pathogens from the Burkholderia and Pseudomonas genera. We examined the rate of drug tolerant persisters in Burkholderia pseudomallei, Burkholderia thailandensis, Burkholderia cepacia complex organisms, and Pseudomonas aeruginosa at mid-log growth in LB broth culture. We found that a fraction of the antibiotic-sensitive cells from every species were tolerant to a 24 h high-dose antibiotic challenge. All tested Burkholderia strains demonstrated a drug tolerant persister population at a rate that was at least 100–500 times higher than P. aeruginosa. When challenged with at least a 10X minimum inhibitory concentration (MIC) 24 h exposure to three different antibiotics with different modes of action we found that in B. pseudomallei Bp82 each of the tree antibiotics revealed different persister fractions at each of two different growth states. This observation suggests that our assay is detecting heterogeneous persister subpopulations. Persistence in B. pseudomallei Bp82 was highly dependent on growth stage, with a surprisingly high persister fraction of >64% of the late stationary phase cells being antibiotic tolerant to 100XMIC cefotaxime. Adaptation of B. pseudomallei to distilled water storage resulted in a population of drug tolerant cells up to 100% of the non-drug-challenged viable cell count in the same cefotaxime assay. Cultivation of B. pseudomallei with a sub-inhibitory concentration of several antibiotics resulted in altered persister fractions within the population relative to cultures lacking the antibiotic. Our study provides insight into the sensitivity of the persister fraction within the population of B. pseudomallei due to environmental variables and suggests diversity within the persister population revealed by

  7. The In vitro Antibiotic Tolerant Persister Population in Burkholderia pseudomallei is Altered by Environmental Factors.

    PubMed

    Nierman, William C; Yu, Yan; Losada, Liliana

    2015-01-01

    Bacterial persistence due to antibiotic tolerance is a critical aspect of antibiotic treatment failure, disease latency, and chronic or reemergent infections. The levels of persisters is especially notable for the opportunistic Gram-negative pathogens from the Burkholderia and Pseudomonas genera. We examined the rate of drug tolerant persisters in Burkholderia pseudomallei, Burkholderia thailandensis, Burkholderia cepacia complex organisms, and Pseudomonas aeruginosa at mid-log growth in LB broth culture. We found that a fraction of the antibiotic-sensitive cells from every species were tolerant to a 24 h high-dose antibiotic challenge. All tested Burkholderia strains demonstrated a drug tolerant persister population at a rate that was at least 100-500 times higher than P. aeruginosa. When challenged with at least a 10X minimum inhibitory concentration (MIC) 24 h exposure to three different antibiotics with different modes of action we found that in B. pseudomallei Bp82 each of the tree antibiotics revealed different persister fractions at each of two different growth states. This observation suggests that our assay is detecting heterogeneous persister subpopulations. Persistence in B. pseudomallei Bp82 was highly dependent on growth stage, with a surprisingly high persister fraction of >64% of the late stationary phase cells being antibiotic tolerant to 100XMIC cefotaxime. Adaptation of B. pseudomallei to distilled water storage resulted in a population of drug tolerant cells up to 100% of the non-drug-challenged viable cell count in the same cefotaxime assay. Cultivation of B. pseudomallei with a sub-inhibitory concentration of several antibiotics resulted in altered persister fractions within the population relative to cultures lacking the antibiotic. Our study provides insight into the sensitivity of the persister fraction within the population of B. pseudomallei due to environmental variables and suggests diversity within the persister population revealed by

  8. [Effect of Inherent Immunity Factors of Development of Antibiotic Tolerance and Survival of Bacterial Populations under Antibiotic Attack].

    PubMed

    Demkina, E V; Loiko, N G; Mulyukin, A L; Smirnova, T A; Gaponov, A M; Pisarev, V M; Tutel'yan, A V; Nikolaev, Yu A; El'-Registan, G I

    2015-01-01

    Effect of human inherent immunity factors of, a gene-encoded antibacterial peptide indolicidin (Ind) and a cytokine interleukin 1 (IL1) on formation of antibiotic-tolerant persister cells surviving in the presence of ciprofloxacin (Cpf, 100 μg/mL) and ampicillin (Amp, 100 μg/mL) in submerged bacterial cultures (Staphylococcus aureus FGA 209P, Escherichia coli K12, and Pseudomonas aeruginosa PAO1) was studied. While Ind in physiological concentrations (0.3 and 3.0 μg/mL) introduced to the lag- or exponential-phase cultures of test organisms exhibited no reliable effect on population growth, the number of persisters increased at 3.0 μg/mL. Bactericidal Ind concentrations (9 μg/mL) suppressed S. aureus growth (-0.1% of surviving cells) with subsequent recovery due to development of the more antibiotic-tolerant white variant. Treatment with Cpf after Ind addition resulted in mutual potentiation of their antimicrobial activity, with the number of S. aureus persisters 2 to 3 orders of magnitude lower than in the case of the antibiotic alone. IL1, another immunity factor, when introduced (0.1-1 ng/mL) to the exponentially growing S. aureus culture (but not to the lag phase culture) had a temporary growth-static effect, with the number of persisters surviving Cpf treatment (100 μg/mL) increasing by 1 to 2 orders of magnitude. Electron microscopy revealed significant alterations in the outer cell envelope layer of surviving S. aureus cells, which should be associated with their changed antigenic properties. Thus, the factors of human inherent immunity have a dose-dependent effect on the growth of bacterial populations. In combination with antibiotics, they exhibit synergism of antimicrobial action (indolicidin) and minimize (indolicidin) or increase (interleukin 1) the frequency of formation of persister cells responsible for survival of a population subjected to an antibiotic attack.

  9. A call for antibiotic alternatives research.

    PubMed

    Stanton, Thaddeus B

    2013-03-01

    The persistence and spread of antibiotic resistance, in conjunction with decreased profitability of new antibiotics, have created the dangerous prospect of ineffective therapies against bacterial diseases. National strategies aimed at discovery, development, and definition of the mechanisms of effective antibiotic alternatives, especially for agricultural applications, should be encouraged. PMID:23473628

  10. Pipeline of Known Chemical Classes of Antibiotics

    PubMed Central

    d’Urso de Souza Mendes, Cristina; de Souza Antunes, Adelaide Maria

    2013-01-01

    Many approaches are used to discover new antibiotic compounds, one of the most widespread being the chemical modification of known antibiotics. This type of discovery has been so important in the development of new antibiotics that most antibiotics used today belong to the same chemical classes as antibiotics discovered in the 1950s and 1960s. Even though the discovery of new classes of antibiotics is urgently needed, the chemical modification of antibiotics in known classes is still widely used to discover new antibiotics, resulting in a great number of compounds in the discovery and clinical pipeline that belong to existing classes. In this scenario, the present article presents an overview of the R&D pipeline of new antibiotics in known classes of antibiotics, from discovery to clinical trial, in order to map out the technological trends in this type of antibiotic R&D, aiming to identify the chemical classes attracting most interest, their spectrum of activity, and the new subclasses under development. The result of the study shows that the new antibiotics in the pipeline belong to the following chemical classes: quinolones, aminoglycosides, macrolides, oxazolidinones, tetracyclines, pleuromutilins, beta-lactams, lipoglycopeptides, polymyxins and cyclic lipopeptides. PMID:27029317

  11. Overcoming the current deadlock in antibiotic research.

    PubMed

    Schäberle, Till F; Hack, Ingrid M

    2014-04-01

    Antibiotic-resistant bacteria are on the rise, making it harder to treat bacterial infections. The situation is aggravated by the shrinking of the antibiotic development pipeline. To finance urgently needed incentives for antibiotic research, creative financing solutions are needed. Public-private partnerships (PPPs) are a successful model for moving forward. PMID:24698433

  12. Overcoming the current deadlock in antibiotic research.

    PubMed

    Schäberle, Till F; Hack, Ingrid M

    2014-04-01

    Antibiotic-resistant bacteria are on the rise, making it harder to treat bacterial infections. The situation is aggravated by the shrinking of the antibiotic development pipeline. To finance urgently needed incentives for antibiotic research, creative financing solutions are needed. Public-private partnerships (PPPs) are a successful model for moving forward.

  13. New business models for antibiotic innovation.

    PubMed

    So, Anthony D; Shah, Tejen A

    2014-05-01

    The increase in antibiotic resistance and the dearth of novel antibiotics have become a growing concern among policy-makers. A combination of financial, scientific, and regulatory challenges poses barriers to antibiotic innovation. However, each of these three challenges provides an opportunity to develop pathways for new business models to bring novel antibiotics to market. Pull-incentives that pay for the outputs of research and development (R&D) and push-incentives that pay for the inputs of R&D can be used to increase innovation for antibiotics. Financial incentives might be structured to promote delinkage of a company's return on investment from revenues of antibiotics. This delinkage strategy might not only increase innovation, but also reinforce rational use of antibiotics. Regulatory approval, however, should not and need not compromise safety and efficacy standards to bring antibiotics with novel mechanisms of action to market. Instead regulatory agencies could encourage development of companion diagnostics, test antibiotic combinations in parallel, and pool and make transparent clinical trial data to lower R&D costs. A tax on non-human use of antibiotics might also create a disincentive for non-therapeutic use of these drugs. Finally, the new business model for antibiotic innovation should apply the 3Rs strategy for encouraging collaborative approaches to R&D in innovating novel antibiotics: sharing resources, risks, and rewards.

  14. The global problem of antibiotic resistance.

    PubMed

    Gootz, Thomas D

    2010-01-01

    . These determinants confer a complex resistance phenotype that is often superimposed on mutations in the primary drug target in the cell. The continued evolution of such a complex array of antibiotic-resistance genes presents a formidable challenge at a time when large pharmaceutical companies have scaled down their presence in the anti-infectives arena.

  15. Get Smart: Know When Antibiotics Work - What Everyone Should Know

    MedlinePlus

    ... What Everyone Should Know What You Can Do Antibiotic Resistance Q&As Fast Facts Antibiotics Quiz Glossary For ... Pharmacists Continuing Education & Curriculum Opportunities Weighing in on Antibiotic Resistance Improving Prescribing Outpatient Antibiotic Stewardship Interventions That Work ...

  16. A three-arm phase III randomised trial assessing, in patients with extensive-disease small-cell lung cancer, accelerated chemotherapy with support of haematological growth factor or oral antibiotics

    PubMed Central

    Sculier, J P; Paesmans, M; Lecomte, J; Van Cutsem, O; Lafitte, J J; Berghmans, T; Koumakis, G; Florin, M C; Thiriaux, J; Michel, J; Giner, V; Berchier, M C; Mommen, P; Ninane, V; Klastersky, J

    2001-01-01

    The European Lung Cancer Working Party (ELCWP) designed a 3-arm phase III randomised trial to determine the role of accelerated chemotherapy in extensive-disease (ED) small-cell lung cancer (SCLC). Eligible patients were randomised between the 3 following arms: (A) Standard chemotherapy with 6 courses of EVI (epirubicin 60 mg m−2, vindesine 3 mg m−2, ifosfamide 5 g m−2; all drugs given on day 1 repeated every three weeks. (B) Accelerated chemotherapy with EVI administered every 2 weeks and GM-CSF support. (C) Accelerated chemotherapy with EVI and oral antibiotics (cotrimoxazole). Primary endpoint was survival. 233 eligible patients were randomised. Chemotherapy could be significantly accelerated in arm B with increased absolute dose-intensity. Best response rates, in the population of evaluable patients, were, respectively for arm A, B and C, 59%, 76% and 70%. The response rate was significantly higher in arm B in comparison to arm A (P = 0.04). There was, however, no survival difference with respective median duration and 2-year rate of 286 days and 5% for arm A, 264 days and 6% for arm B and 264 days and 6% for arm C. Severe thrombopenia occurred more frequently in arm B but without an increased rate of bleeding. Non-severe infections were more frequent in arm B and severe infections were less frequent in arm C. Our trial failed to demonstrate, in ED-SCLC, a survival benefit of chemotherapy acceleration by using GM-CSF support.   http://www.bjcancer.com PMID:11720426

  17. [Mechanism of action of antibiotics:some examples].

    PubMed

    Michel-Briand, Y

    1978-01-01

    Antibiotics are very commonly used substances to eradicate bacterial infections by bacteriostatic or even bactericid effect. They act at a very specific stage (target), although other less important or secondary interactions can occur. We studied the interaction of three antibiotic families (beta-lactamins, aminosides, rifampicin) with bacterial cell. Penicillin disturbs the cell wall synthesis and more accurately the glycopeptide (or murein) formation, a substance giving rigidity or shape to bacteria. It acts in the late phase of murein-biosynthesis, when N-acetyl glucosamin -- N-acetyl muramic acid L ala -D glu M-DAP (L lys) -D ala -D ala are linked together by the peptide part, under the effect of several enzymes, particularly transpeptidase and DD-carboxy-peptidase. It would appear that beta-lactame-thiazolidine rings have a steric analogy with dipeptide D-alanyl D-alanine. The result would be that the enzyme would act on the antibiotic instead of peptide: the consequence would be inhibition of the peptidic link, giving an abnormal murein, and an incomplete cell wall i.e. fragile bacteria. Aminosides, particularly Streptomycin, link themselves to 30 S subunit of bacterial ribosome. In this case, it seems that it is a 3''OH function which reacts with lysine (from S 12 protein part of 30 S subunit). The consequence is an alteration in the RNA messager lecture, and a false traduction and consequently protein biosynthesis stops with a decrease of polyribosomes and of the formation of inert 70 S ribosome. Rifamycins, and particularly Rifampicin act by inhibition of RNA messager synthesis. One molecule of antibiotic links itself to one molecule of RNA messager : hydroxyl and cetone function in C1 Cs C21 C23 and "ansa" bridge link to beta subunit of RNA polymerase. This linkage gives a conformational change to the RNA polymerase-DNA complex, inhibiting the catalytic action of this enzyme, and consequently stopping RNA messager and protein synthesis. The study of the

  18. A mathematical model for expected time to extinction of pathogenic bacteria through antibiotic

    NASA Astrophysics Data System (ADS)

    Ghosh, M. K.; Nandi, S.; Roy, P. K.

    2016-04-01

    Application of antibiotics in human system to prevent bacterial diseases like Gastritis, Ulcers, Meningitis, Pneumonia and Gonorrhea are indispensable. Antibiotics saved innumerable lives and continue to be a strong support for therapeutic application against pathogenic bacteria. In human system, bacterial diseases occur when pathogenic bacteria gets into the body and begin to reproduce and crowd out healthy bacteria. In this process, immature bacteria releases enzyme which is essential for bacterial cell-wall biosynthesis. After complete formation of cell wall, immature bacteria are converted to mature or virulent bacteria which are harmful to us during bacterial infections. Use of antibiotics as drug inhibits the bacterial cell wall formation. After application of antibiotics within body, the released bacterial enzyme binds with antibiotic molecule instead of its functional site during the cell wall synthesis in a competitive inhibition approach. As a consequence, the bacterial cell-wall formation as well as maturation process of pathogenic bacteria is halted and the disease is cured with lysis of bacterial cells. With this idea, a mathematical model has been developed in the present research investigation to review the inhibition of biosynthesis of bacterial cell wall by the application of antibiotics as drug in the light of enzyme kinetics. This approach helps to estimate the expected time to extinction of the pathogenic bacteria. Our mathematical approach based on the enzyme kinetic model for finding out expected time to extinction contributes favorable results for understanding of disease dynamics. Analytical and numerical results based on simulated findings validate our mathematical model.

  19. A quorum sensing small volatile molecule promotes antibiotic tolerance in bacteria.

    PubMed

    Que, Yok-Ai; Hazan, Ronen; Strobel, Benjamin; Maura, Damien; He, Jianxin; Kesarwani, Meenu; Panopoulos, Panagiotis; Tsurumi, Amy; Giddey, Marlyse; Wilhelmy, Julie; Mindrinos, Michael N; Rahme, Laurence G

    2013-01-01

    Bacteria can be refractory to antibiotics due to a sub-population of dormant cells, called persisters that are highly tolerant to antibiotic exposure. The low frequency and transience of the antibiotic tolerant "persister" trait has complicated elucidation of the mechanism that controls antibiotic tolerance. In this study, we show that 2' Amino-acetophenone (2-AA), a poorly studied but diagnostically important small, volatile molecule produced by the recalcitrant gram-negative human pathogen Pseudomonas aeruginosa, promotes antibiotic tolerance in response to quorum-sensing (QS) signaling. Our results show that 2-AA mediated persister cell accumulation occurs via alteration of the expression of genes involved in the translational capacity of the cell, including almost all ribosomal protein genes and other translation-related factors. That 2-AA promotes persisters formation also in other emerging multi-drug resistant pathogens, including the non 2-AA producer Acinetobacter baumannii implies that 2-AA may play an important role in the ability of gram-negative bacteria to tolerate antibiotic treatments in polymicrobial infections. Given that the synthesis, excretion and uptake of QS small molecules is a common hallmark of prokaryotes, together with the fact that the translational machinery is highly conserved, we posit that modulation of the translational capacity of the cell via QS molecules, may be a general, widely distributed mechanism that promotes antibiotic tolerance among prokaryotes.

  20. A Quorum Sensing Small Volatile Molecule Promotes Antibiotic Tolerance in Bacteria

    PubMed Central

    Strobel, Benjamin; Maura, Damien; He, Jianxin; Kesarwani, Meenu; Panopoulos, Panagiotis; Tsurumi, Amy; Giddey, Marlyse; Wilhelmy, Julie; Mindrinos, Michael N.; Rahme, Laurence G.

    2013-01-01

    Bacteria can be refractory to antibiotics due to a sub-population of dormant cells, called persisters that are highly tolerant to antibiotic exposure. The low frequency and transience of the antibiotic tolerant “persister” trait has complicated elucidation of the mechanism that controls antibiotic tolerance. In this study, we show that 2’ Amino-acetophenone (2-AA), a poorly studied but diagnostically important small, volatile molecule produced by the recalcitrant gram-negative human pathogen Pseudomonas aeruginosa, promotes antibiotic tolerance in response to quorum-sensing (QS) signaling. Our results show that 2-AA mediated persister cell accumulation occurs via alteration of the expression of genes involved in the translational capacity of the cell, including almost all ribosomal protein genes and other translation-related factors. That 2-AA promotes persisters formation also in other emerging multi-drug resistant pathogens, including the non 2-AA producer Acinetobacter baumannii implies that 2-AA may play an important role in the ability of gram-negative bacteria to tolerate antibiotic treatments in polymicrobial infections. Given that the synthesis, excretion and uptake of QS small molecules is a common hallmark of prokaryotes, together with the fact that the translational machinery is highly conserved, we posit that modulation of the translational capacity of the cell via QS molecules, may be a general, widely distributed mechanism that promotes antibiotic tolerance among prokaryotes. PMID:24367477

  1. Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?

    PubMed

    Brown, David

    2015-12-01

    Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.

  2. Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?

    PubMed

    Brown, David

    2015-12-01

    Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation. PMID:26493767

  3. Effect of Surfactants on Antibiotic Resistance

    PubMed Central

    Suling, William J.; O'Leary, William M.

    1975-01-01

    The effectiveness of surfactants as potentiators of antibiotic activity on several resistant strains of bacteria, selected from clinical sources and laboratory collections, was studied using a tube dilution assay. Bacterial strains included members of the Enterobacteriaceae and staphylococci. Cetyltrimethylammonium bromide (CTAB), Tween 80 (Tw80), a mixture of n-alkyldimethyl betaines (L14), and alpha-(2,4,5-trichlorophenoxy) propionic acid (TCP) were tested in combination with pencillin G (PenG), methicillin (Met), streptomycin (Sm), polymyxin B (PmB), and chlortetracycline (CTC). Growth response to the drug combinations was compared with the response to each drug alone. CTAB and L14 but not Tw80 or TCP were found to potentiate the activity of CTC on strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Studies on the inhibition of protein synthesis by CTC in cells of a strain of E. coli suggested that the surfactants increased the uptake of antibiotic into the cells. CTAB and L14 almost completely sensitized strains of P. mirabilis, Serratia marcescens, K. pneumoniae, and E. coli to PmB. With the exception of K. pneumoniae, TCP was also effective in potentiating the activity of PmB on the above strains whereas Tw80 showed potentiation only with a strain of E. coli. CTAB and L14 but not TCP or Tw80 potentiated the activity of PenG but not Met on strains of staphylococci. Studies of penicillinase in the cells suggested that the surfactants inhibited the formation of this enzyme possibly at the level of induction. None of the surfactants were found to potentiate the activity of Sm. PMID:1101823

  4. Antibiotic Tolerance Induced by Lactoferrin in Clinical Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients

    PubMed Central

    Andrés, María T.; Viejo-Diaz, Mónica; Pérez, Francisco; Fierro, José F.

    2005-01-01

    Lactoferrin-induced cell depolarization and a delayed tobramycin-killing effect on Pseudomonas aeruginosa cells were correlated. This antibiotic tolerance effect (ATE) reflects the ability of a defense protein to modify the activity of an antibiotic as a result of its modulatory effect on bacterial physiology. P. aeruginosa isolates from cystic fibrosis patients showed higher ATE values (≤6-fold) than other clinical strains. PMID:15793153

  5. Surface modeling of soil antibiotics.

    PubMed

    Shi, Wen-jiao; Yue, Tian-xiang; Du, Zheng-ping; Wang, Zong; Li, Xue-wen

    2016-02-01

    Large numbers of livestock and poultry feces are continuously applied into soils in intensive vegetable cultivation areas, and then some veterinary antibiotics are persistent existed in soils and cause health risk. For the spatial heterogeneity of antibiotic residues, developing a suitable technique to interpolate soil antibiotic residues is still a challenge. In this study, we developed an effective interpolator, high accuracy surface modeling (HASM) combined vegetable types, to predict the spatial patterns of soil antibiotics, using 100 surface soil samples collected from an intensive vegetable cultivation area located in east of China, and the fluoroquinolones (FQs), including ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX), were analyzed as the target antibiotics. The results show that vegetable type is an effective factor to be combined to improve the interpolator performance. HASM achieves less mean absolute errors (MAEs) and root mean square errors (RMSEs) for total FQs (NFX+CFX+EFX), NFX, CFX and EFX than kriging with external drift (KED), stratified kriging (StK), ordinary kriging (OK) and inverse distance weighting (IDW). The MAE of HASM for FQs is 55.1 μg/kg, and the MAEs of KED, StK, OK and IDW are 99.0 μg/kg, 102.8 μg/kg, 106.3 μg/kg and 108.7 μg/kg, respectively. Further, RMSE simulated by HASM for FQs (CFX, EFX and NFX) are 106.2 μg/kg (88.6 μg/kg, 20.4 μg/kg and 39.2 μg/kg), and less 30% (27%, 22% and 36%), 33% (27%, 27% and 43%), 38% (34%, 23% and 41%) and 42% (32%, 35% and 51%) than the ones by KED, StK, OK and IDW, respectively. HASM also provides better maps with more details and more consistent maximum and minimum values of soil antibiotics compared with the measured data. The better performance can be concluded that HASM takes the vegetable type information as global approximate information, and takes local sampling data as its optimum control constraints.

  6. Surface modeling of soil antibiotics.

    PubMed

    Shi, Wen-jiao; Yue, Tian-xiang; Du, Zheng-ping; Wang, Zong; Li, Xue-wen

    2016-02-01

    Large numbers of livestock and poultry feces are continuously applied into soils in intensive vegetable cultivation areas, and then some veterinary antibiotics are persistent existed in soils and cause health risk. For the spatial heterogeneity of antibiotic residues, developing a suitable technique to interpolate soil antibiotic residues is still a challenge. In this study, we developed an effective interpolator, high accuracy surface modeling (HASM) combined vegetable types, to predict the spatial patterns of soil antibiotics, using 100 surface soil samples collected from an intensive vegetable cultivation area located in east of China, and the fluoroquinolones (FQs), including ciprofloxacin (CFX), enrofloxacin (EFX) and norfloxacin (NFX), were analyzed as the target antibiotics. The results show that vegetable type is an effective factor to be combined to improve the interpolator performance. HASM achieves less mean absolute errors (MAEs) and root mean square errors (RMSEs) for total FQs (NFX+CFX+EFX), NFX, CFX and EFX than kriging with external drift (KED), stratified kriging (StK), ordinary kriging (OK) and inverse distance weighting (IDW). The MAE of HASM for FQs is 55.1 μg/kg, and the MAEs of KED, StK, OK and IDW are 99.0 μg/kg, 102.8 μg/kg, 106.3 μg/kg and 108.7 μg/kg, respectively. Further, RMSE simulated by HASM for FQs (CFX, EFX and NFX) are 106.2 μg/kg (88.6 μg/kg, 20.4 μg/kg and 39.2 μg/kg), and less 30% (27%, 22% and 36%), 33% (27%, 27% and 43%), 38% (34%, 23% and 41%) and 42% (32%, 35% and 51%) than the ones by KED, StK, OK and IDW, respectively. HASM also provides better maps with more details and more consistent maximum and minimum values of soil antibiotics compared with the measured data. The better performance can be concluded that HASM takes the vegetable type information as global approximate information, and takes local sampling data as its optimum control constraints. PMID:26613514

  7. Infection, antibiotics, and preterm delivery.

    PubMed

    Locksmith, G; Duff, P

    2001-10-01

    The relationship between genital tract infection and preterm delivery has been established on the basis of biochemical, microbiological, and clinical evidence. In theory, pathogenic bacteria may ascend from the lower reproductive tract into the uterus, and the resulting inflammation leads to preterm labor, rupture of the membranes, and birth. A growing body of evidence suggests that preterm labor and/rupture of the membranes are triggered by micro-organisms in the genital tract and by the host response to these organisms, ie, elaboration of cytokines and proteolytic enzymes. Epidemiologic and in vitro studies do not prove a cause-and-effect relationship between infection and preterm birth. However, the preponderance of evidence indicates that treatment of asymptomatic bacteriuria and symptomatic lower genital tract infections such as bacterial vaginosis (BV), trichomoniasis, gonorrhea, and chlamydia will lower the risk of preterm delivery. Based on current evidence, pregnant women who note an abnormal vaginal discharge should be tested for BV, trichomonas, gonorrhea, and chlamydia. Those who test positive should be treated appropriately. A 3- to 7-day course of antibiotic treatment for asymptomatic bacteriuria during pregnancy is clinically indicated to reduce the risk of pyelonephritis and preterm delivery. Routine screening for chlamydia and gonorrhea should be performed for women at high risk of acquiring sexually transmitted diseases. The practice of routine screening for BV in asymptomatic women who are at low risk for preterm delivery cannot be supported based on evidence from the literature. Routine screening for asymptomatic bacteriuria during pregnancy is cost-effective, particularly in high-prevalence populations. The results of antibiotic trials for the treatment of preterm labor have been inconsistent. In the absence of reasonable evidence that antimicrobial therapy leads to significant prolongation of pregnancy in the setting of preterm labor

  8. Antibiotic resistance: a growing and multifaceted problem.

    PubMed

    Clark, L

    Antibiotic resistance is an increasing problem worldwide that is exacerbated by the overuse and misuse of antibiotics. Patients, pharmaceutical marketing, and the use of antibiotics in veterinary medicine and animal husbandry are important factors to consider in the emergence of resistance. Infection control measures to prevent the spread of antibiotic-resistant bacteria are compromised by poor compliance to basic measures such as handwashing and standards of environmental cleanliness. Wider epidemiological factors such as global travel and complacency towards public health must also be considered. This article aims to improve understanding of antibiotic resistance and suggests ways in which nurses can contribute towards the strategy to address the problem.

  9. Review of antibiotics and indications for prophylaxis.

    PubMed

    Weiss, Adam; Dym, Harry

    2012-01-01

    Antibiotic prophylaxis to prevent infective endocarditis has been controversial through the years, with various changes made to recommendations provided to treating physicians and dentists. The dentist must always use his or her best judgment when applying any guideline. However, it is important to remember that the guidelines may be cited in any malpractice litigation as evidence of the standard of care. Early diagnosis with prompt treatment with effective antimicrobial therapy is the best way to lower the mortality and morbidity. When prescribing antibiotics, the clinician must realize that the overprescription of antibiotics has led to resistance to antibiotic regimens and the rise of antibiotic-resistant bacteria.

  10. Overcoming Resistance to β-Lactam Antibiotics

    PubMed Central

    Worthington, Roberta J.; Melander, Christian

    2013-01-01

    β-Lactam antibiotics are one of the most important antibiotic classes but are plagued by problems of resistance and the development of new β-lactam antibiotics through side chain modification of existing β-lactam classes is not keeping pace with resistance development. In this perspective we summarize small molecule strategies to overcome resistance to β-lactam antibiotics. These approaches include the development of β-lactamase inhibitors and compounds that interfere with the ability of the bacteria to sense an antibiotic threat and activate their resistance mechanisms. PMID:23530949

  11. Antibiotic overuse and resistance in dermatology.

    PubMed

    Chon, Susan Y; Doan, Hung Q; Mays, Rana Majd; Singh, Selina M; Gordon, Rachel A; Tyring, Stephen K

    2012-01-01

    Antibiotics have a significant role in dermatology, treating a wide range of diseases, including acne, rosacea, inflammatory skin conditions and skin structure infections, such as cellulitis, folliculitis, carbuncles, and furuncles. Because of their consistent use, utility, and availability, antibiotics are susceptible to overuse within the medical practice, and, specific to this discussion, in the dermatologic setting. The issue of continuously increasing risk of antibiotic resistance remains an important concern to the dermatologist. The scope of this review will be to provide an overview of the common antibiotics used in the dermatologic setting with an emphasis on identifying areas of overuse, reported bacterial resistance, and discussion of clinical management aimed at decreasing antibiotic resistance.

  12. [Is monotherapy with β-lactam antibiotics still up to date? New aspects for treatment of severe infections].

    PubMed

    Heizmann, P; Lode, H; Heizmann, W R

    2012-02-01

    Mortality of sepsis is still high. Crucial for therapeutic response are the early start of treatment as well as the choice of antibiotics or antibiotic combinations. β-lactam antibiotics with bactericidal mode of action are often recommended in guidelines. But this antibiotic class can trigger the immune system to a maximum by releasing cell wall components or exotoxins. This may lead to a worsening of the patient's clinical situation. In contrast, antibiotics with bacteriostatic action often inhibit bacterial protein synthesis with decrease of production of virulence factors and minimize release of cell wall components. The purpose of this review is to summarise the significance of some bacteriostatic antibiotics and to discuss whether a combination of bactericidal and bacteriostatic agents may improve the course of the illness.

  13. Fumarate-Mediated Persistence of Escherichia coli against Antibiotics

    PubMed Central

    Kim, Jun-Seob; Cho, Da-Hyeong; Heo, Paul; Jung, Suk-Chae; Park, Myungseo; Oh, Eun-Joong; Sung, Jaeyun; Kim, Pan-Jun; Lee, Suk-Chan; Lee, Dae-Hee; Lee, Sarah; Lee, Choong Hwan; Shin, Dongwoo

    2016-01-01

    Bacterial persisters are a small fraction of quiescent cells that survive in the presence of lethal concentrations of antibiotics. They can regrow to give rise to a new population that has the same vulnerability to the antibiotics as did the parental population. Although formation of bacterial persisters in the presence of various antibiotics has been documented, the molecular mechanisms by which these persisters tolerate the antibiotics are still controversial. We found that amplification of the fumarate reductase operon (FRD) in Escherichia coli led to a higher frequency of persister formation. The persister frequency of E. coli was increased when the cells contained elevated levels of intracellular fumarate. Genetic perturbations of the electron transport chain (ETC), a metabolite supplementation assay, and even the toxin-antitoxin-related hipA7 mutation indicated that surplus fumarate markedly elevated the E. coli persister frequency. An E. coli strain lacking succinate dehydrogenase (SDH), thereby showing a lower intracellular fumarate concentration, was killed ∼1,000-fold more effectively than the wild-type strain in the stationary phase. It appears that SDH and FRD represent a paired system that gives rise to and maintains E. coli persisters by producing and utilizing fumarate, respectively. PMID:26810657

  14. Use of antibiotics in plant agriculture.

    PubMed

    Stockwell, V O; Duffy, B

    2012-04-01

    Antibiotics are essential for control of bacterial diseases of plants, especially fire blight of pear and apple and bacterial spot of peach. Streptomycin is used in several countries; the use of oxytetracycline, oxolinic acid and gentamicin is limited to only a few countries. Springtime antibiotic sprays suppress pathogen growth on flowers and leaf surfaces before infection; after infection, antibiotics are ineffective. Antibiotics are applied when disease risk is high, and consequently the majority of orchards are not treated annually. In 2009 in the United States, 16,465 kg (active ingredient) was applied to orchards, which is 0.12% of the total antibiotics used in animal agriculture. Antibiotics are active on plants for less than a week, and significant residues have not been found on harvested fruit. Antibiotics have been indispensable for crop protection in the United States for more than 50 years without reports of adverse effects on human health or persistent impacts on the environment. PMID:22849276

  15. Resistance to Antibiotics Mediated by Target Alterations

    NASA Astrophysics Data System (ADS)

    Spratt, Brian G.

    1994-04-01

    The development of resistance to antibiotics by reductions in the affinities of their enzymatic targets occurs most rapidly for antibiotics that inactivate a single target and that are not analogs of substrate. In these cases of resistance (for example, resistance to rifampicin), numerous single amino acid substitutions may provide large decreases in the affinity of the target for the antibiotic, leading to clinically significant levels of resistance. Resistance due to target alterations should occur much more slowly for those antibiotics (penicillin, for example) that inactivate multiple targets irreversibly by acting as close analogs of substrate. Resistance to penicillin because of target changes has emerged, by unexpected mechanisms, only in a limited number of species. However, inactivating enzymes commonly provide resistance to antibiotics that, like penicillin, are derived from natural products, although such enzymes have not been found for synthetic antibiotics. Thus, the ideal antibiotic would be produced by rational design, rather than by the modification of a natural product.

  16. Use of antibiotics in plant agriculture.

    PubMed

    Stockwell, V O; Duffy, B

    2012-04-01

    Antibiotics are essential for control of bacterial diseases of plants, especially fire blight of pear and apple and bacterial spot of peach. Streptomycin is used in several countries; the use of oxytetracycline, oxolinic acid and gentamicin is limited to only a few countries. Springtime antibiotic sprays suppress pathogen growth on flowers and leaf surfaces before infection; after infection, antibiotics are ineffective. Antibiotics are applied when disease risk is high, and consequently the majority of orchards are not treated annually. In 2009 in the United States, 16,465 kg (active ingredient) was applied to orchards, which is 0.12% of the total antibiotics used in animal agriculture. Antibiotics are active on plants for less than a week, and significant residues have not been found on harvested fruit. Antibiotics have been indispensable for crop protection in the United States for more than 50 years without reports of adverse effects on human health or persistent impacts on the environment.

  17. Designing Safer and Greener Antibiotics

    PubMed Central

    Jordan, Andrew; Gathergood, Nicholas

    2013-01-01

    Since the production of the first pharmaceutically active molecules at the beginning of the 1900s, drug molecules and their metabolites have been observed in the environment in significant concentrations. In this review, the persistence of antibiotics in the environment and their associated effects on ecosystems, bacterial resistance and health effects will be examined. Solutions to these problems will also be discussed, including the pharmaceutical industries input, green chemistry, computer modeling and representative ionic liquid research. PMID:27029311

  18. Planktonic Aggregates of Staphylococcus aureus Protect against Common Antibiotics

    PubMed Central

    Haaber, Jakob; Cohn, Marianne Thorup; Frees, Dorte; Andersen, Thorbjørn Joest; Ingmer, Hanne

    2012-01-01

    Bacterial cells are mostly studied during planktonic growth although in their natural habitats they are often found in communities such as biofilms with dramatically different physiological properties. We have examined another type of community namely cellular aggregates observed in strains of the human pathogen Staphylococcus aureus. By laser-diffraction particle–size analysis (LDA) we show, for strains forming visible aggregates, that the aggregation starts already in the early exponential growth phase and proceeds until post-exponential phase where more than 90% of the population is part of the aggregate community. Similar to some types of biofilm, the structural component of S. aureus aggregates is the polysaccharide intercellular adhesin (PIA). Importantly, PIA production correlates with the level of aggregation whether altered through mutations or exposure to sub-inhibitory concentrations of selected antibiotics. While some properties of aggregates resemble those of biofilms including increased mutation frequency and survival during antibiotic treatment, aggregated cells displayed higher metabolic activity than planktonic cells or cells in biofilm. Thus, our data indicate that the properties of cells in aggregates differ in some aspects from those in biofilms. It is generally accepted that the biofilm life style protects pathogens against antibiotics and the hostile environment of the host. We speculate that in aggregate communities S. aureus increases its tolerance to hazardous environments and that the combination of a biofilm-like environment with mobility has substantial practical and clinical importance. PMID:22815921

  19. Antibiotics and the gut microbiota

    PubMed Central

    Modi, Sheetal R.; Collins, James J.; Relman, David A.

    2014-01-01

    Antibiotics have been a cornerstone of innovation in the fields of public health, agriculture, and medicine. However, recent studies have shed new light on the collateral damage they impart on the indigenous host-associated communities. These drugs have been found to alter the taxonomic, genomic, and functional capacity of the human gut microbiota, with effects that are rapid and sometimes persistent. Broad-spectrum antibiotics reduce bacterial diversity while expanding and collapsing membership of specific indigenous taxa. Furthermore, antibiotic treatment selects for resistant bacteria, increases opportunities for horizontal gene transfer, and enables intrusion of pathogenic organisms through depletion of occupied natural niches, with profound implications for the emergence of resistance. Because these pervasive alterations can be viewed as an uncoupling of mutualistic host-microbe relationships, it is valuable to reconsider antimicrobial therapies in the context of an ecological framework. Understanding the biology of competitive exclusion, interspecies protection, and gene flow of adaptive functions in the gut environment may inform the design of new strategies that treat infections while preserving the ecology of our beneficial constituents. PMID:25271726

  20. [Antibiotic treatment of clostridial colitis].

    PubMed

    Beneš, J; Polívková, S

    2016-01-01

    The advantages and disadvantages of various antibiotics used in the treatment of Clostridium difficile infection (CDI) are compared with respect to their pharmacokinetic and pharmacodynamic properties. Recommendations are made for their optimal use in clinical practice. Metronidazole is suitable for the treatment of mild forms of CDI which are essentially self-limiting. Vancomycin kills clostridia reliably but the treatment is encumbered with considerable risk of recurrence. This can be decreased by shortening the treatment to seven days and then switching to a (pulse, taper, chaser) regimen to prevent recurrence or by active restoration of the intestinal ecosystem (fecal transplant). Fidaxomicin works faster than vancomycin and is associated with a lower risk of recurrence. Thus, it can be profitably used in patients with impending ileus and also in those whose medical condition does not allow prolonged treatment. The duration of fidaxomicin treatment could be reduced to as few as five days. Rifaximin does not have a clear place in the treatment of CDI because no compelling data are available on its efficacy in this disease. The risk of resistance is also important. Tigecycline is a promising antibiotic for parenteral use. According to the available data, it should be more effective than intravenous metronidazole which has been considered the drug of choice.Clostridial colitis is associated with intestinal dysmicrobia which is the major cause of recurrence. Severe dysmicrobia cannot be treated by antibiotics but only by gut flora restoration; stool transplant from a healthy donor is the only proven therapy for this condition. PMID:27246640

  1. Probiotics and antibiotics in IBD.

    PubMed

    Sokol, Harry

    2014-01-01

    The involvement of the gut microbiota in the pathogenesis of IBD is supported by many findings and is thus now commonly acknowledged. The imbalance in the composition of the microbiota (dysbiosis) observed in IBD patients is one of the strongest arguments and provides the rationale for a therapeutic manipulation of the gut microbiota. The tools available to achieve this goal include fecal microbiota transplantation, but antibiotics and probiotics have been the most used one until now. Although antibiotics have shown some efficacy in inducing remission in Crohn's disease (CD) and ulcerative colitis (UC), as well as preventing postoperative relapse in CD, they are not currently recommended for the treatment of IBD except for septic complications, notably because of long-term tolerance and ecological issues. Some probiotics have been shown to be as good as 5-aminosalicylic acid to maintain remission in mild-to-moderate UC, but have been disappointing until now in CD in all tested indications. In pouchitis, antibiotics and probiotics have shown efficacy for inducing and maintaining remission, respectively. Targeting the gut microbiota in IBD is an attractive strategy. Current efforts to better understand the host-microbiota interactions in physiological as well as disease settings might lead to the development of rational-based treatments.

  2. Desensitization to antibiotics in children.

    PubMed

    Cernadas, Josefina R

    2013-02-01

    Drug hypersensitivity reactions can occur to almost all drugs and antibiotics are among the most common cause for this kind of reactions. Drug hypersensitivity may affect any organ or system, and manifestations range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. In case of infection, there is usually a safe antibiotic alternative. Nonetheless, in some cases, no alternative treatment exists for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance to a drug which can only be maintained by continuous administration of the medication responsible for the hypersensitivity reaction. Desensitization is mainly performed in IgE-mediated reactions. Increasing doses of the implicated drug are administered over a short period of time, until the therapeutic dose is achieved and tolerated. Very few studies confined to children are found in literature. Most of them are case reports. In general, the proposed desensitization schemes are similar to those used in adults differing only in the final dose administered. The purpose of this study is to review desensitization to antibiotics in children presenting and discussing three clinical practical cases of desensitization in this age group.

  3. Activation of Antibiotic Production in Bacillus spp. by Cumulative Drug Resistance Mutations.

    PubMed

    Tojo, Shigeo; Tanaka, Yukinori; Ochi, Kozo

    2015-12-01

    Bacillus subtilis strains produce a wide range of antibiotics, including ribosomal and nonribosomal peptide antibiotics, as well as bacilysocin and neotrehalosadiamine. Mutations in B. subtilis strain 168 that conferred resistance to drugs such as streptomycin and rifampin resulted in overproduction of the dipeptide antibiotic bacilysin. Cumulative drug resistance mutations, such as mutations in the mthA and rpsL genes, which confer low- and high-level resistance, respectively, to streptomycin, and mutations in rpoB, which confer resistance to rifampin, resulted in cells that overproduced bacilysin. Transcriptional analysis demonstrated that the enhanced transcription of biosynthesis genes was responsible for the overproduction of bacilysin. This approach was effective also in activating the cryptic genes of Bacillus amyloliquefaciens, leading to actual production of antibiotic(s).

  4. Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics.

    PubMed

    Qi, Jianzhao; Liu, Jin; Wan, Dan; Cai, You-Sheng; Wang, Yinghu; Li, Shunying; Wu, Pan; Feng, Xuan; Qiu, Guofu; Yang, Sheng-Ping; Chen, Wenqing; Deng, Zixin

    2015-09-01

    Polyoxin and nikkomycin are naturally occurring peptidyl nucleoside antibiotics with potent antifungal bioactivity. Both exhibit similar structural features, having a nucleoside skeleton and one or two peptidyl moieties. Combining the refactoring of the polyoxin producer Streptomyces aureochromogenes with import of the hydroxypyridylhomothreonine pathway of nikkomycin allows the targeted production of three designer nucleoside antibiotics designated as nikkoxin E, F, and G. These structures were determined by NMR and/or high resolution mass spectrometry. Remarkably, the introduction of an extra copy of the nikS gene encoding an ATP-dependent ligase significantly enhanced the production of the designer antibiotics. Moreover, all three nikkoxins displayed improved bioactivity against several pathogenic fungi as compared with the naturally-occurring antibiotics. These data provide a feasible model for high efficiency generation of nucleoside antibiotics related to polyoxins and nikkomycins in a polyoxin cell factory via synthetic biology strategy.

  5. A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S

    PubMed Central

    Shiver, Anthony L.; Kritikos, George; Li, Bo; Krogan, Nevan; Typas, Athanasios

    2016-01-01

    Fighting antibiotic resistance requires a deeper understanding of the genetic factors that determine the antibiotic susceptibility of bacteria. Here we describe a chemical-genomic screen in Escherichia coli K-12 that was designed to discover new aspects of antibiotic resistance by focusing on a set of 26 antibiotics and other stresses with poorly characterized mode-of-action and determinants of resistance. We show that the screen identifies new resistance determinants for these antibiotics including a common signature from two antimicrobials, kasugamycin and blasticidin S, used to treat crop diseases like rice blast and fire blight. Following this signature, we further investigated the mechanistic basis for susceptibility to kasugamycin and blasticidin S in E. coli using both genetic and biochemical approaches. We provide evidence that these compounds hijack an overlapping set of peptide ABC-importers to enter the bacterial cell. Loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens. PMID:27355376

  6. A Chemical-Genomic Screen of Neglected Antibiotics Reveals Illicit Transport of Kasugamycin and Blasticidin S.

    PubMed

    Shiver, Anthony L; Osadnik, Hendrik; Kritikos, George; Li, Bo; Krogan, Nevan; Typas, Athanasios; Gross, Carol A

    2016-06-01

    Fighting antibiotic resistance requires a deeper understanding of the genetic factors that determine the antibiotic susceptibility of bacteria. Here we describe a chemical-genomic screen in Escherichia coli K-12 that was designed to discover new aspects of antibiotic resistance by focusing on a set of 26 antibiotics and other stresses with poorly characterized mode-of-action and determinants of resistance. We show that the screen identifies new resistance determinants for these antibiotics including a common signature from two antimicrobials, kasugamycin and blasticidin S, used to treat crop diseases like rice blast and fire blight. Following this signature, we further investigated the mechanistic basis for susceptibility to kasugamycin and blasticidin S in E. coli using both genetic and biochemical approaches. We provide evidence that these compounds hijack an overlapping set of peptide ABC-importers to enter the bacterial cell. Loss of uptake may be an underappreciated mechanism for the development of kasugamycin resistance in bacterial plant pathogens. PMID:27355376

  7. Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria.

    PubMed

    Nguyen, Dao; Joshi-Datar, Amruta; Lepine, Francois; Bauerle, Elizabeth; Olakanmi, Oyebode; Beer, Karlyn; McKay, Geoffrey; Siehnel, Richard; Schafhauser, James; Wang, Yun; Britigan, Bradley E; Singh, Pradeep K

    2011-11-18

    Bacteria become highly tolerant to antibiotics when nutrients are limited. The inactivity of antibiotic targets caused by starvation-induced growth arrest is thought to be a key mechanism producing tolerance. Here we show that the antibiotic tolerance of nutrient-limited and biofilm Pseudomonas aeruginosa is mediated by active responses to starvation, rather than by the passive effects of growth arrest. The protective mechanism is controlled by the starvation-signaling stringent response (SR), and our experiments link SR-mediated tolerance to reduced levels of oxidant stress in bacterial cells. Furthermore, inactivating this protective mechanism sensitized biofilms by several orders of magnitude to four different classes of antibiotics and markedly enhanced the efficacy of antibiotic treatment in experimental infections. PMID:22096200

  8. Antibiotics and the expression of staphylococcal virulence.

    PubMed

    Gemmell, C G

    1995-08-01

    The last 25 years have witnessed a continuing interest in staphylococci as causes of human infection even though over 100 years have elapsed since their discovery. This has been due in part to the recognition of new disease entities such as scalded skin syndrome, toxic shock syndrome and various infections due to coagulase-negative staphylococci. Development of antimicrobial agents has not solved the problem of these infections partly because of their mediation by novel toxins and partly due to the emergence of multiple drug resistance. However study of the interaction between certain antibiotics and staphylococci in vitro and in vivo has provided new knowledge concerning the role of cell wall-associated and soluble virulence factors in the pathogenesis of staphylococcal disease.

  9. Antibiotics induce redox-related physiological alterations as part of their lethality.

    PubMed

    Dwyer, Daniel J; Belenky, Peter A; Yang, Jason H; MacDonald, I Cody; Martell, Jeffrey D; Takahashi, Noriko; Chan, Clement T Y; Lobritz, Michael A; Braff, Dana; Schwarz, Eric G; Ye, Jonathan D; Pati, Mekhala; Vercruysse, Maarten; Ralifo, Paul S; Allison, Kyle R; Khalil, Ahmad S; Ting, Alice Y; Walker, Graham C; Collins, James J

    2014-05-20

    Deeper understanding of antibiotic-induced physiological responses is critical to identifying means for enhancing our current antibiotic arsenal. Bactericidal antibiotics with diverse targets have been hypothesized to kill bacteria, in part by inducing production of damaging reactive species. This notion has been supported by many groups but has been challenged recently. Here we robustly test the hypothesis using biochemical, enzymatic, and biophysical assays along with genetic and phenotypic experiments. We first used a novel intracellular H2O2 sensor, together with a chemically diverse panel of fluorescent dyes sensitive to an array of reactive species to demonstrate that antibiotics broadly induce redox stress. Subsequent gene-expression analyses reveal that complex antibiotic-induced oxidative stress responses are distinct from canonical responses generated by supraphysiological levels of H2O2. We next developed a method to quantify cellular respiration dynamically and found that bactericidal antibiotics elevate oxygen consumption, indicating significant alterations to bacterial redox physiology. We further show that overexpression of catalase or DNA mismatch repair enzyme, MutS, and antioxidant pretreatment limit antibiotic lethality, indicating that reactive oxygen species causatively contribute to antibiotic killing. Critically, the killing efficacy of antibiotics was diminished under strict anaerobic conditions but could be enhanced by exposure to molecular oxygen or by the addition of alternative electron acceptors, indicating that environmental factors play a role in killing cells physiologically primed for death. This work provides direct evidence that, downstream of their target-specific interactions, bactericidal antibiotics induce complex redox alterations that contribute to cellular damage and death, thus supporting an evolving, expanded model of antibiotic lethality.

  10. Association between clinical antibiotic resistance and susceptibility of Pseudomonas in the cystic fibrosis lung

    PubMed Central

    Jansen, Gunther; Mahrt, Niels; Tueffers, Leif; Barbosa, Camilo; Harjes, Malte; Adolph, Gernot; Friedrichs, Anette; Krenz-Weinreich, Annegret; Rosenstiel, Philip; Schulenburg, Hinrich

    2016-01-01

    Background and objectives: Cystic fibrosis patients suffer from chronic lung infections that require long-term antibiotic therapy. Pseudomonas readily evolve resistance, rendering antibiotics ineffective. In vitro experiments suggest that resistant bacteria may be treated by exploiting their collateral sensitivity to other antibiotics. Here, we investigate correlations of sensitivity and resistance profiles of Pseudomonas aeruginosa that naturally adapted to antibiotics in the cystic fibrosis lung. Methodology: Resistance profiles for 13 antibiotics were obtained using broth dilution, E-test and VITEK mass spectroscopy. Genetic variants were determined from whole-genome sequences and interrelationships among isolates were analyzed using 13 MLST loci. Result: Our study focused on 45 isolates from 13 patients under documented treatment with antibiotics. Forty percent of these were clinically resistant and 15% multi-drug resistant. Colistin resistance was found once, despite continuous colistin treatment and even though colistin resistance can readily evolve experimentally in the laboratory. Patients typically harbored multiple genetically and phenotypically distinct clones. However, genetically similar clones often had dissimilar resistance profiles. Isolates showed mutations in genes encoding cell wall synthesis, alginate production, efflux pumps and antibiotic modifying enzymes. Cross-resistance was commonly observed within antibiotic classes and between aminoglycosides and β-lactam antibiotics. No evidence was found for consistent phenotypic resistance to one antibiotic and sensitivity to another within one genotype. Conclusions and implications: Evidence supporting potential collateral sensitivity in clinical P. aeruginosa isolates remains equivocal. However, cross-resistance within antibiotic classes is common. Colistin therapy is promising since resistance to it was rare despite its intensive use in the studied patients. PMID:27193199

  11. Endopeptidase-Mediated Beta Lactam Tolerance

    PubMed Central

    Dörr, Tobias; Davis, Brigid M.; Waldor, Matthew K.

    2015-01-01

    In many bacteria, inhibition of cell wall synthesis leads to cell death and lysis. The pathways and enzymes that mediate cell lysis after exposure to cell wall-acting antibiotics (e.g. beta lactams) are incompletely understood, but the activities of enzymes that degrade the cell wall (‘autolysins’) are thought to be critical. Here, we report that Vibrio cholerae, the cholera pathogen, is tolerant to antibiotics targeting cell wall synthesis. In response to a wide variety of cell wall- acting antibiotics, this pathogen loses its rod shape, indicative of cell wall degradation, and becomes spherical. Genetic analyses revealed that paradoxically, V. cholerae survival via sphere formation required the activity of D,D endopeptidases, enzymes that cleave the cell wall. Other autolysins proved dispensable for this process. Our findings suggest the enzymes that mediate cell wall degradation are critical for determining bacterial cell fate - sphere formation vs. lysis – after treatment with antibiotics that target cell wall synthesis. PMID:25884840

  12. A Broad-Spectrum Antibiofilm Peptide Enhances Antibiotic Action against Bacterial Biofilms

    PubMed Central

    Reffuveille, Fany; de la Fuente-Núñez, César; Mansour, Sarah

    2014-01-01

    Biofilm-related infections account for at least 65% of all human infections, but there are no available antimicrobials that specifically target biofilms. Their elimination by available treatments is inefficient since biofilm cells are between 10- and 1,000-fold more resistant to conventional antibiotics than planktonic cells. Here we describe the synergistic interactions, with different classes of antibiotics, of a recently characterized antibiofilm peptide, 1018, to potently prevent and eradicate bacterial biofilms formed by multidrug-resistant ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Combinations of peptide 1018 and the antibiotic ceftazidime, ciprofloxacin, imipenem, or tobramycin were synergistic in 50% of assessments and decreased by 2- to 64-fold the concentration of antibiotic required to treat biofilms formed by Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Salmonella enterica, and methicillin-resistant Staphylococcus aureus. Furthermore, in flow cell biofilm studies, combinations of low, subinhibitory levels of the peptide (0.8 μg/ml) and ciprofloxacin (40 ng/ml) decreased dispersal and triggered cell death in mature P. aeruginosa biofilms. In addition, short-term treatments with the peptide in combination with ciprofloxacin prevented biofilm formation and reduced P. aeruginosa PA14 preexisting biofilms. PCR studies indicated that the peptide suppressed the expression of various antibiotic targets in biofilm cells. Thus, treatment with the peptide represents a novel strategy to potentiate antibiotic activity against biofilms formed by multidrug-resistant pathogens. PMID:24982074

  13. Antibiotic Modification of Native Grafts: Improving upon nature's scaffolds

    NASA Astrophysics Data System (ADS)

    Ketonis, Constantinos

    -like cells with no increased toxicity. Furthermore, the antibiotic-modified allograft incorporated well into tibial defects in the rat. Finally, this construct was efficacious in decreasing the severity of infection and host reaction when impacted in an in vivo model of allograft-associated infection. Thus, our proposed modification in surface design serves as a starting point for the development of a new generation of bone grafts that are biologically active at sites of physiological importance.

  14. The expression of antibiotic resistance genes in antibiotic-producing bacteria.

    PubMed

    Mak, Stefanie; Xu, Ye; Nodwell, Justin R

    2014-08-01

    Antibiotic-producing bacteria encode antibiotic resistance genes that protect them from the biologically active molecules that they produce. The expression of these genes needs to occur in a timely manner: either in advance of or concomitantly with biosynthesis. It appears that there have been at least two general solutions to this problem. In many cases, the expression of resistance genes is tightly linked to that of antibiotic biosynthetic genes. In others, the resistance genes can be induced by their cognate antibiotics or by intermediate molecules from their biosynthetic pathways. The regulatory mechanisms that couple resistance to antibiotic biosynthesis are mechanistically diverse and potentially relevant to the origins of clinical antibiotic resistance.

  15. Development of antibiotics and the future of marine microorganisms to stem the tide of antibiotic resistance

    PubMed Central

    Kasanah, Noer; Hamann, Mark T

    2016-01-01

    Antibiotics remain essential tools in the control of infectious diseases. With the emergence of new diseases, resistant forms of diseases such as tuberculosis and malaria, as well as the emergence of multidrug-resistant bacteria, it has become essential to develop novel antibiotics. Development of the existing antibiotics involved three strategies, including discovery of new target sites, modification of existing antibiotic structures, and the identification of new resources for novel antibiotics. Marine microorganisms have clearly become an essential new resource in the discovery of new antibiotic leads. PMID:15600239

  16. Antibiotic persistence: the role of spontaneous DNA repair response.

    PubMed

    Debbia, E A; Roveta, S; Schito, A M; Gualco, L; Marchese, A

    2001-01-01

    Persisters are a small proportion of a bacterial population that exists in a physiological state permitting survival despite the lethal activity of antibiotics. To explain this phenomenon, it has been suggested that persisters are bacteria repairing spontaneous errors of DNA synthesis. To verify this assumption, Escherichia coli AB1157 and its lexA3 derivative were exposed to a dose 6x MIC of various antibiotics representative of different molecular mechanisms of action (ampicillin, ceftriaxone, meropenem, amikacin, ciprofloxacin). Bacterial cell counts, after 24 hr of exposure to the antimicrobials, revealed a reduction of about 90% of viable organisms in the lexA3 strains in comparison to the lexA+. In several cases, the number of colony-forming units decreased below the limit of assay. This behavior was noted with all antibiotics used, alone or in combination (amikacin plus ceftriaxone and amikacin plus ciprofloxacin). The same experiments were repeated using E. coli AB1157 cultured in the presence of mitomycin C (0.25x MIC), and the number of survivors exceeded by about 90% the values found in the nonexposed control. In contrast, in the sulA background, mitomycin C reacted synergically with all the antibiotics tested causing a strong reduction of the survivors in comparison with the control. The addition of chloramphenicol (0.125x MIC), on the contrary, caused a reduction of the number of survivors of about 90%. These findings indicate that, when DNA repair is active (a mechanism known to block cell division), the number of survivors is greater than that observed with lexA3. Thus, in addition to other possible explanations, persisters might be a fraction of bacteria that during antibiotic treatment are not growing because they are repairing spontaneous errors of DNA synthesis.

  17. Antibiotics

    NASA Astrophysics Data System (ADS)

    Anhalt, John P.

    A 28-year-old man was transferred to our hospital and underwent surgery for resection of an aortic graft infected with Klebsiella pneumoniae. Antimicrobial therapy consisted of amikacin, cefazolin, chloramphenicol, sulfamethoxazole, and trimethoprim. A request for amikacin and sulfamethoxazole assays was received by the laboratory along with information that the patient had received tobramycin until 24 h before the serum was obtained.

  18. [Effectiveness and tolerance of antibiotics in pediatrics patients].

    PubMed

    Zeman, Krzysztof

    2011-05-01

    Antibiotics represent the most widely prescribed therapeutic agents. Preschool children being most exposed to antibiotic drugs, especially in the community setting. Unnecessary antibiotic prescribing remains the cardinal contributing factor to the development of antibiotic resistance. Early antibiotic exposure, especially to broad-spectrum antibiotics, may suppress the developing immune system and produce a reduced anti-allergic response. Early antibiotic use in children is associated with an increased risk for asthma.

  19. Mechanisms of Resistance to Aminoglycoside Antibiotics: Overview and Perspectives

    PubMed Central

    Garneau-Tsodikova, Sylvie

    2015-01-01

    Aminoglycoside (AG) antibiotics are used to treat many Gram-negative and some Gram-positive infections and, importantly, multidrug-resistant tuberculosis. Among various bacterial species, resistance to AGs arises through a variety of intrinsic and acquired mechanisms. The bacterial cell wall serves as a natural barrier for small molecules such as AGs and may be further fortified via acquired mutations. Efflux pumps work to expel AGs from bacterial cells, and modifications here too may cause further resistance to AGs. Mutations in the ribosomal target of AGs, while rare, also contribute to resistance. Of growing clinical prominence is resistance caused by ribosome methyltransferases. By far the most widespread mechanism of resistance to AGs is the inactivation of these antibiotics by AG-modifying enzymes. We provide here an overview of these mechanisms by which bacteria become resistant to AGs and discuss their prevalence and potential for clinical relevance. PMID:26877861

  20. Laser based enhancement of susceptibility of bacteria to antibiotic

    NASA Astrophysics Data System (ADS)

    Reznick, Yana; Banin, Ehud; Lipovsky, Anat; Lubart, Rachel; Zalevsky, Zeev

    2012-03-01

    Our objective is to test the effect of pulsed (Q-switched) and continuous wave (CW) laser light at wavelength of 532nm on the viability of free-living stationary phase bacteria with and without gentamicin (an antibiotic) treatment. Free living stationary phase gram negative bacteria (Pseudomonas aeruginosa strain PAO1) was immersed in Luria Broth (LB) solution and exposed to Q-switched and CW lasers with and without the addition of the antibiotic gentamicin. Cell viability was determined at different time points. Laser treatment alone did not reduce cell viability compared to untreated control and the gentamicin treatment alone only resulted in a 0.5 log reduction in the viable count for P. aeruginosa. The combined laser and gentamicin treatment, however, resulted in a synergistic effect and viability was reduced by 8 log's for P. aeruginosa PAO1.

  1. Allantoin catabolism influences the production of antibiotics in Streptomyces coelicolor.

    PubMed

    Navone, Laura; Casati, Paula; Licona-Cassani, Cuauhtémoc; Marcellin, Esteban; Nielsen, Lars K; Rodriguez, Eduardo; Gramajo, Hugo

    2014-01-01

    Purines are a primary source of carbon and nitrogen in soil; however, their metabolism is poorly understood in Streptomyces. Using a combination of proteomics, metabolomics, and metabolic engineering, we characterized the allantoin pathway in Streptomyces coelicolor. When cells grew in glucose minimal medium with allantoin as the sole nitrogen source, quantitative proteomics identified 38 enzymes upregulated and 28 downregulated. This allowed identifying six new functional enzymes involved in allantoin metabolism in S. coelicolor. From those, using a combination of biochemical and genetic engineering tools, it was found that allantoinase (EC 3.5.2.5) and allantoicase (EC 3.5.3.4) are essential for allantoin metabolism in S. coelicolor. Metabolomics showed that under these growth conditions, there is a significant intracellular accumulation of urea and amino acids, which eventually results in urea and ammonium release into the culture medium. Antibiotic production of a urease mutant strain showed that the catabolism of allantoin, and the subsequent release of ammonium, inhibits antibiotic production. These observations link the antibiotic production impairment with an imbalance in nitrogen metabolism and provide the first evidence of an interaction between purine metabolism and antibiotic biosynthesis.

  2. Plasmids Carried by Antibiotic-Resistant Marine Bacteria

    PubMed Central

    Sizemore, Ronald K.; Colwell, R. R.

    1977-01-01

    Antibiotic-resistant bacteria were isolated from seawater samples collected in the Atlantic Ocean off the southeastern coast of the United States. Large numbers of antibiotic-resistant bacterial strains were found to be present in harbor and inshore waters; however, the percentage of resistant strains was higher for several seawater samples collected offshore than for those collected near shore. Bacteria resistant to tetracycline, chloramphenicol, and streptomycin were found in nearly all samples collected, including samples from 200 miles (about 522 km) offshore and at depths to 8,200 m. Sediment samples, in general, were found to contain smaller populations of resistant strains as compared with the seawater samples examined. Antibiotic-resistant bacteria exhibiting phenetic characteristics common to autochthonous marine bacterial species were examined in detail, and several of the isolates exhibited unstable antibiotic resistance, which was transferable to recipient Escherichia coli cells. Deoxyribonucleic acid preparations from 10 strains examined by ethidium bromide-cesium chloride density sedimentation revealed that 6 of the strains contained covalently closed circular plasmid deoxyribonucleic acid. PMID:334064

  3. Bacteria-mediated effects of antibiotics on Daphnia nutrition.

    PubMed

    Gorokhova, Elena; Rivetti, Claudia; Furuhagen, Sara; Edlund, Anna; Ek, Karin; Breitholtz, Magnus

    2015-05-01

    In polluted environments, contaminant effects may be manifested via both direct toxicity to the host and changes in its microbiota, affecting bacteria-host interactions. In this context, particularly relevant is exposure to antibiotics released into environment. We examined effects of the antibiotic trimethoprim on microbiota of Daphnia magna and concomitant changes in the host feeding. In daphnids exposed to 0.25 mg L(-1) trimethoprim for 24 h, the microbiota was strongly affected, with (1) up to 21-fold decrease in 16S rRNA gene abundance and (2) a shift from balanced communities dominated by Curvibacter, Aquabacterium, and Limnohabitans in controls to significantly lower diversity under dominance of Pelomonas in the exposed animals. Moreover, decreased feeding and digestion was observed in the animals exposed to 0.25-2 mg L(-1) trimethoprim for 48 h and then fed 14C-labeled algae. Whereas the proportion of intact algal cells in the guts increased with increased trimethoprim concentration, ingestion and incorporation rates as well as digestion and incorporation efficiencies decreased significantly. Thus, antibiotics may impact nontarget species via changes in their microbiota leading to compromised nutrition and, ultimately, growth. These bacteria-mediated effects in nontarget organisms may not be unique for antibiotics, but also relevant for environmental pollutants of various nature.

  4. In silico analysis of different generation β lactams antibiotics with penicillin binding protein-2 of Neisseria meningitidis for curing meningococcal disease.

    PubMed

    Tripathi, Vijay; Tripathi, Pooja; Srivastava, Navita; Gupta, Dwijendra

    2014-12-01

    Neisseria meningitidis is a gram negative, diplococcic pathogen responsible for the meningococcal disease and fulminant septicemia. Penicillin-binding proteins-2 (PBPs) is crucial for the cell wall biosynthesis during cell proliferation of N. meningitidis and these are the target for β-lactam antibiotics. For many years penicillin has been recognized as the antibiotic for meningococcal disease but the meningococcus has seemed to be antibiotic resistance. In the present work we have verified the molecular interaction of Penicillin binding protein-2 N. meningitidis to different generation of β-lactam antibiotics and concluded that the third generation of β-lactam antibiotics shows efficient binding with Penicillin binding protein-2 of N. meningitidis. On the basis of binding efficiency and inhibition constant, ceftazidime emerged as the most efficient antibiotic amongst the other advanced β-lactam antibiotics against Penicillin-binding protein-2 of N. meningitidis.

  5. Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy.

    PubMed

    Lee, Sie Huey; Teo, Jeanette; Heng, Desmond; Ng, Wai Kiong; Zhao, Yanli; Tan, Reginald B H

    2016-04-01

    Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 μm-3.4 ± 0.1 μm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa.

  6. Tailored Antibiotic Combination Powders for Inhaled Rotational Antibiotic Therapy.

    PubMed

    Lee, Sie Huey; Teo, Jeanette; Heng, Desmond; Ng, Wai Kiong; Zhao, Yanli; Tan, Reginald B H

    2016-04-01

    Respiratory lung infections due to multidrug-resistant (MDR) superbugs are on a global upsurge and have very grim clinical outcomes. Their MDR profile makes therapeutic options extremely limited. Although a highly toxic antibiotic, colistin, is favored today as a "last-line" therapeutic against these hard-to-treat MDR pathogens, it is fast losing its effectiveness. This work therefore seeks to identify and tailor-make useful combination regimens (that are potentially rotatable and synergistic) as attractive alternative strategies to address the rising rates of drug resistance. Three potentially rotatable ternary dry powder inhaler constructs (each involving colistin and 2 other different-classed antibiotics chosen from rifampicin, meropenem, and tigecycline) were identified (with distinct complementary killing mechanisms), coformulated via spray drying, evaluated on their aerosol performance using a Next-Generation Impactor and tested for their efficacies against a number of MDR pathogens. The powder particles were of respirable size (d50, 3.1 ± 0.3 μm-3.4 ± 0.1 μm) and predominantly crumpled in morphology. When dispersed via a model dry powder inhaler (Aerolizer(®)) at 60 L/min, the powders showed concomitant in vitro deposition with fine particle fractions of ∼53%-70%. All formulations were successfully tested in the laboratory to be highly effective against the MDR pathogens. In addition, a favorable synergistic interaction was detected across all 3 formulations when tested against MDR Pseudomonas aeruginosa. PMID:27019964

  7. Microbiological effects of sublethal levels of antibiotics.

    PubMed

    Andersson, Dan I; Hughes, Diarmaid

    2014-07-01

    The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

  8. Treatment of acne with topical antibiotics.

    PubMed

    Frank, S B

    1977-06-01

    The introduction of topical antibiotics for acne vulgaris has ushered in a new era in the treatment of this troublesome disorder. Tetracycline, erythromycin, and clindamycin can now be prepared in lotion form in vehicles that are capable of carrying the antibiotic into the follicular canal, where the primary lesion of acne occurs. Topical antibiotics are practically as effective as oral antibiotics in treating acne and are particularly useful for mild papular acne of puberty and early adolescence and papular-pustular acne of adult women. Use of topical antibiotics avoids the possibility of the adverse effects of systemic therapy; the side effects from the formulations reported here are negligible. Above all, antibiotic lotions do not produce the dryness and scaling that occur with most other topical acne preparations.

  9. Probiotics or antibiotics: future challenges in medicine.

    PubMed

    Nami, Yousef; Haghshenas, Babak; Abdullah, Norhafizah; Barzegari, Abolfazl; Radiah, Dayang; Rosli, Rozita; Khosroushahi, Ahmad Yari

    2015-02-01

    Genetic and environmental factors can affect the intestinal microbiome and microbial metabolome. Among these environmental factors, the consumption of antibiotics can significantly change the intestinal microbiome of individuals and consequently affect the corresponding metagenome. The term 'probiotics' is related to preventive medicine rather than therapeutic procedures and is, thus, considered the opposite of antibiotics. This review discusses the challenges between these opposing treatments in terms of the following points: (i) antibiotic resistance, the relationship between antibiotic consumption and microbiome diversity reduction, antibiotic effect on the metagenome, and disease associated with antibiotics; and (ii) probiotics as living drugs, probiotic effect on epigenetic alterations, and gut microbiome relevance to hygiene indulgence. The intestinal microbiome is more specific for individuals and may be affected by environmental alterations and the occurrence of diseases.

  10. Partial recovery of microbiomes after antibiotic treatment.

    PubMed

    Raymond, Frédéric; Déraspe, Maxime; Boissinot, Maurice; Bergeron, Michel G; Corbeil, Jacques

    2016-09-01

    Antibiotics profoundly affect the gut microbiome and modulate microbial communities. We recently observed that antimicrobial drugs also impact the abundance and distribution of antibiotic resistance genes. In this addendum, we reanalyze our ∼1 trillion nucleotide shotgun metagenomic dataset to quantify comprehensive genomic differences at the sequence level before and after antibiotic treatment. We show that 7 day exposure to cefprozil leads to a statistically significant loss of metagenome sequences. Recovery of gut microbiomes 3 months after antibiotherapy was characterized by the emergence of new genome sequences not observed prior to antibiotic exposure. Participants with low initial gut microbiome diversity had an increased amount of sequences related to antibiotic resistance. Therefore, we suggest that while the taxonomical composition of microbiomes is partially affected by the antibiotic, the genomic content and population structure of bacterial communities is noticeably impacted. PMID:27494088

  11. Antibiotic stewardship: a focus on ambulatory care.

    PubMed

    Gangat, M Azhar; Hsu, Jennifer L

    2015-01-01

    Antibiotic resistance is one of the major health threats facing modern medicine. While there are many tactics to address this issue, antibiotic stewardship has been shown effective in reducing antimicrobial resistance, adverse drug effects, mortality and health care cost. Most antibiotic stewardship programs have evolved within acute care settings where the bulk of resistant infections are identified. Unfortunately, hospitals are just the tip of the iceberg in terms of overall antibiotic use. The vast majority of the antibiotic prescriptions are dispensed in ambulatory care settings, making this a critical target for stewardship programs. This article discusses the global need for antibiotic stewardship, highlights the importance of outpatient stewardship, and discusses strategies and challenges for implementation of stewardship in community settings.

  12. Antibiotic stewardship programmes--what's missing?

    PubMed

    Charani, Esmita; Cooke, Jonathan; Holmes, Alison

    2010-11-01

    Inappropriate antibiotic use and antibiotic resistance are now major global issues. Antimicrobial stewardship programmes are increasingly being used to optimize antibiotic prescribing in acute care. The central tenet of these programmes tends to be policy and guidelines aimed at prescribers. However, rules and guidelines alone may not be sufficient to bring about effective and sustainable optimization of practice. Best practice needs to be positively reinforced by an environment that facilitates and supports optimal prescribing choices, i.e. a 'choice architecture' that makes prudent antibiotic prescribing the path of least resistance. To make prudent antibiotic management an integral part of the behaviour of all healthcare professionals and to bring about quality improvement it is necessary to adopt a whole-system approach. To do this it is necessary first to understand the factors that influence antibiotic management and prescribing.

  13. Prophylactic antibiotics for curettage abortion.

    PubMed

    Grimes, D A; Schulz, K F; Cates, W

    1984-11-15

    Opinion is divided as to the advisability of routine use of prophylactic antibiotics for curettage abortion. Six studies, including three randomized clinical trials, suggest that prophylaxis reduces infectious morbidity associated with curettage abortions by about one half. Three other studies, two involving prophylaxis for instillation abortions and one involving a vaginal antiseptic for curettage abortion, support the hypothesis that antimicrobial prophylaxis reduces morbidity. Tetracyclines are commonly used for this purpose. The cost of routine prophylaxis even with an expensive tetracycline would appear to be offset by the savings in direct and indirect costs. Prophylaxis may help prevent both short-term morbidity and potential late sequelae, such as ectopic pregnancy and infertility.

  14. Blast from the Past: Reassessing Forgotten Translation Inhibitors, Antibiotic Selectivity, and Resistance Mechanisms to Aid Drug Development.

    PubMed

    Arenz, Stefan; Wilson, Daniel N

    2016-01-01

    Protein synthesis is a major target within the bacterial cell for antibiotics. Investigations into ribosome-targeting antibiotics have provided much needed functional and structural insight into their mechanism of action. However, the increasing prevalence of multi-drug-resistant bacteria has limited the utility of our current arsenal of clinically relevant antibiotics, highlighting the need for the development of new classes. Recent structural studies have characterized a number of antibiotics discovered decades ago that have unique chemical scaffolds and/or utilize novel modes of action to interact with the ribosome and inhibit translation. Additionally, structures of eukaryotic cytoplasmic and mitochondrial ribosomes have provided further structural insight into the basis for specificity and toxicity of antibiotics. Together with our increased understanding of bacterial resistance mechanisms, revisiting our treasure trove of "forgotten" antibiotics could pave the way for the next generation of antimicrobial agents. PMID:26585390

  15. Blast from the Past: Reassessing Forgotten Translation Inhibitors, Antibiotic Selectivity, and Resistance Mechanisms to Aid Drug Development.

    PubMed

    Arenz, Stefan; Wilson, Daniel N

    2016-01-01

    Protein synthesis is a major target within the bacterial cell for antibiotics. Investigations into ribosome-targeting antibiotics have provided much needed functional and structural insight into their mechanism of action. However, the increasing prevalence of multi-drug-resistant bacteria has limited the utility of our current arsenal of clinically relevant antibiotics, highlighting the need for the development of new classes. Recent structural studies have characterized a number of antibiotics discovered decades ago that have unique chemical scaffolds and/or utilize novel modes of action to interact with the ribosome and inhibit translation. Additionally, structures of eukaryotic cytoplasmic and mitochondrial ribosomes have provided further structural insight into the basis for specificity and toxicity of antibiotics. Together with our increased understanding of bacterial resistance mechanisms, revisiting our treasure trove of "forgotten" antibiotics could pave the way for the next generation of antimicrobial agents.

  16. Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one

    PubMed Central

    Bouley, Renee; Kumarasiri, Malika; Peng, Zhihong; Otero, Lisandro H.; Song, Wei; Suckow, Mark A.; Schroeder, Valerie A.; Wolter, William R.; Lastochkin, Elena; Antunes, Nuno T.; Pi, Hualiang; Vakulenko, Sergei; Hermoso, Juan A.; Chang, Mayland; Mobashery, Shahriar

    2015-01-01

    In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections. PMID:25629446

  17. The spatial profiles and metabolic capabilities of microbial populations impact the growth of antibiotic-resistant mutants.

    PubMed

    Kaushik, Karishma S; Ratnayeke, Nalin; Katira, Parag; Gordon, Vernita D

    2015-06-01

    Antibiotic resistance adversely affects clinical and public health on a global scale. Using the opportunistic human pathogen Pseudomonas aeruginosa, we show that increasing the number density of bacteria, on agar containing aminoglycoside antibiotics, can non-monotonically impact the survival of antibiotic-resistant mutants. Notably, at high cell densities, mutant survival is inhibited. A wide range of bacterial species can inhibit antibiotic-resistant mutants. Inhibition results from the metabolic breakdown of amino acids, which results in alkaline by-products. The consequent increase in pH acts in conjunction with aminoglycosides to mediate inhibition. Our work raises the possibility that the manipulation of microbial population structure and nutrient environment in conjunction with existing antibiotics could provide therapeutic approaches to combat antibiotic resistance.

  18. The spatial profiles and metabolic capabilities of microbial populations impact the growth of antibiotic-resistant mutants

    PubMed Central

    Kaushik, Karishma S.; Ratnayeke, Nalin; Katira, Parag; Gordon, Vernita D.

    2015-01-01

    Antibiotic resistance adversely affects clinical and public health on a global scale. Using the opportunistic human pathogen Pseudomonas aeruginosa, we show that increasing the number density of bacteria, on agar containing aminoglycoside antibiotics, can non-monotonically impact the survival of antibiotic-resistant mutants. Notably, at high cell densities, mutant survival is inhibited. A wide range of bacterial species can inhibit antibiotic-resistant mutants. Inhibition results from the metabolic breakdown of amino acids, which results in alkaline by-products. The consequent increase in pH acts in conjunction with aminoglycosides to mediate inhibition. Our work raises the possibility that the manipulation of microbial population structure and nutrient environment in conjunction with existing antibiotics could provide therapeutic approaches to combat antibiotic resistance. PMID:25972434

  19. Sensitivity of cellulolytic bacteria to antibiotics.

    PubMed

    Szegi, J; El-Din, H G

    1977-01-01

    The sensitivity of eight cellulolytic bacterial strains to eight antibiotics was tested. The results showed that, in general, the strains belonging to Cytophaga, Cellvibrio, and Cellfalcicula are more sensitive to antibiotics than those strains that belong to Sporocytophaga and Cellulomonas. The inhibitory activity of the tested antibiotics, though differing with different strains, showed the following categories: tetracycline, erythromycin, and chloromycetin were most active, kanamycin, streptomycin, and neomycin were intermediate, while novobiocin and penicillin showed low activity. PMID:414477

  20. CDC Grand Rounds: Getting Smart About Antibiotics.

    PubMed

    Demirjian, Alicia; Sanchez, Guillermo V; Finkelstein, Jonathan A; Ling, Shari M; Srinivasan, Arjun; Pollack, Lori A; Hicks, Lauri A; Iskander, John K

    2015-08-21

    Each year in the United States, approximately two million persons become infected with antibiotic-resistant bacteria, at least 23,000 persons die as a direct result of these infections, and many more die from conditions complicated by a resistant infection. Antibiotic-resistant infections contribute to poor health outcomes, higher health care costs, and use of more toxic treatments. Although emerging resistance mechanisms are being identified and resistant infections are on the rise, new antibiotic development has slowed considerably.

  1. A novel antibiotic, sohbumycin. Taxonomy, fermentation, isolation and physico-chemical and biological characteristics.

    PubMed

    Umezawa, I; Tronquet, C; Funayama, S; Okada, K; Komiyama, K

    1985-08-01

    A new antibiotic sohbumycin, was isolated from the culture broth of Streptomyces sp. No. 82-85. It appeared to belong to the peptide lactone type of antibiotics from physico-chemical studies and has an empirical formula of C31H47N8O10Cl. In in vitro studies, the antibiotic was found to possess potent cytocidal activity against HeLa S3 cells and antimicrobial activities against Gram-positive bacteria with MIC values about 0.3-0.6 microgram/ml, but showed no activity on the Gram-negative bacteria, yeast and fungi tested. PMID:3840156

  2. A Site-Specific Recombinase-Based Method to Produce Antibiotic Selectable Marker Free Transgenic Cattle

    PubMed Central

    Tong, Qi; Liu, Xu; Su, Feng; Quan, Fusheng; Guo, Zekun; Zhang, Yong

    2013-01-01

    Antibiotic selectable marker genes have been widely used to generate transgenic animals. Once transgenic animals have been obtained, the selectable marker is no longer necessary but raises public concerns regarding biological safety. The aim of this study was to prepare competent antibiotic selectable marker free transgenic cells for somatic cell nuclear transfer (SCNT). PhiC31 intergrase was used to insert a transgene cassette into a “safe harbor” in the bovine genome. Then, Cre recombinase was employed to excise the selectable marker under the monitoring of a fluorescent double reporter. By visually tracking the phenotypic switch from red to green fluorescence, antibiotic selectable marker free cells were easily detected and sorted by fluorescence-activated cell sorting. For safety, we used phiC31 mRNA and cell-permeant Cre protein in this study. When used as donor nuclei for SCNT, these safe harbor integrated marker-free transgenic cells supported a similar developmental competence of SCNT embryos compared with that of non-transgenic cells. After embryo transfer, antibiotic selectable marker free transgenic cattle were generated and anti-bacterial recombinant human β-defensin-3 in milk was detected during their lactation period. Thus, this approach offers a rapid and safe alternative to produce antibiotic selectable marker free transgenic farm animals, thereby making it a valuable tool to promote the healthy development and welfare of transgenic farm animals. PMID:23658729

  3. A site-specific recombinase-based method to produce antibiotic selectable marker free transgenic cattle.

    PubMed

    Yu, Yuan; Wang, Yongsheng; Tong, Qi; Liu, Xu; Su, Feng; Quan, Fusheng; Guo, Zekun; Zhang, Yong

    2013-01-01

    Antibiotic selectable marker genes have been widely used to generate transgenic animals. Once transgenic animals have been obtained, the selectable marker is no longer necessary but raises public concerns regarding biological safety. The aim of this study was to prepare competent antibiotic selectable marker free transgenic cells for somatic cell nuclear transfer (SCNT). PhiC31 intergrase was used to insert a transgene cassette into a "safe harbor" in the bovine genome. Then, Cre recombinase was employed to excise the selectable marker under the monitoring of a fluorescent double reporter. By visually tracking the phenotypic switch from red to green fluorescence, antibiotic selectable marker free cells were easily detected and sorted by fluorescence-activated cell sorting. For safety, we used phiC31 mRNA and cell-permeant Cre protein in this study. When used as donor nuclei for SCNT, these safe harbor integrated marker-free transgenic cells supported a similar developmental competence of SCNT embryos compared with that of non-transgenic cells. After embryo transfer, antibiotic selectable marker free transgenic cattle were generated and anti-bacterial recombinant human β-defensin-3 in milk was detected during their lactation period. Thus, this approach offers a rapid and safe alternative to produce antibiotic selectable marker free transgenic farm animals, thereby making it a valuable tool to promote the healthy development and welfare of transgenic farm animals.

  4. Tackling antibiotic resistance: the environmental framework.

    PubMed

    Berendonk, Thomas U; Manaia, Célia M; Merlin, Christophe; Fatta-Kassinos, Despo; Cytryn, Eddie; Walsh, Fiona; Bürgmann, Helmut; Sørum, Henning; Norström, Madelaine; Pons, Marie-Noëlle; Kreuzinger, Norbert; Huovinen, Pentti; Stefani, Stefania; Schwartz, Thomas; Kisand, Veljo; Baquero, Fernando; Martinez, José Luis

    2015-05-01

    Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment.

  5. Antibiotic treatments and microbes in the gut.

    PubMed

    Macfarlane, Sandra

    2014-04-01

    Antibiotic therapies are important in combating disease-causing microorganisms and maintaining host health. It is widely accepted that exposure of the gut microbiota to antibiotics can lead to decreased susceptibility and the development of multi-drug-resistant disease-causing organisms, which can be a major clinical problem. It is also important to consider that antibiotics not only target pathogenic bacteria in the gut, but also can have damaging effects on the ecology of commensal species. This can reduce intrinsic colonization resistance and contribute to problems with antibiotic resistance, including lateral transfer of resistance genes. Our knowledge of the impact of antibiotic treatment on the ecology of the normal microbiota has been increased by recent advances in molecular methods and use of in vitro model systems to investigate the impact of antibiotics on the biodiversity of gut populations and the spread of antibiotic resistance. These highlight the need for more detailed structural and functional information on the long-term antibiotic-associated alterations in the gut microbiome, and spread of antibiotic resistance genes. This will be crucial for the development of strategies, such as targeted therapeutics, probiotics, prebiotics and synbiotics, to prevent perturbations in the gut microbiota, the restoration of beneficial species and improvements in host health.

  6. Antibiotics: natural products essential to human health.

    PubMed

    Demain, Arnold L

    2009-11-01

    For more than 50 years, natural products have served us well in combating infectious bacteria and fungi. Microbial and plant secondary metabolites helped to double our life span during the 20th century, reduced pain and suffering, and revolutionized medicine. Most antibiotics are either (i) natural products of microorganisms, (ii) semi-synthetically produced from natural products, or (iii) chemically synthesized based on the structure of the natural products. Production of antibiotics began with penicillin in the late 1940s and proceeded with great success until the 1970-1980s when it became harder and harder to discover new and useful products. Furthermore, resistance development in pathogens became a major problem, which is still with us today. In addition, new pathogens are continually emerging and there are still bacteria that are not eliminated by any antibiotic, e.g., Pseudomonas aeruginosa. In addition to these problems, many of the major pharmaceutical companies have abandoned the antibiotic field, leaving much of the discovery efforts to small companies, new companies, and the biotechnology industries. Despite these problems, development of new antibiotics has continued, albeit at a much lower pace than in the last century. We have seen the (i) appearance of newly discovered antibiotics (e.g., candins), (ii) development of old but unutilized antibiotics (e.g., daptomycin), (iii) production of new semi-synthetic versions of old antibiotics (e.g., glycylcyclines, streptogrammins), as well as the (iv) very useful application of old but underutilized antibiotics (e.g., teicoplanin).

  7. Tackling antibiotic resistance: the environmental framework.

    PubMed

    Berendonk, Thomas U; Manaia, Célia M; Merlin, Christophe; Fatta-Kassinos, Despo; Cytryn, Eddie; Walsh, Fiona; Bürgmann, Helmut; Sørum, Henning; Norström, Madelaine; Pons, Marie-Noëlle; Kreuzinger, Norbert; Huovinen, Pentti; Stefani, Stefania; Schwartz, Thomas; Kisand, Veljo; Baquero, Fernando; Martinez, José Luis

    2015-05-01

    Antibiotic resistance is a threat to human and animal health worldwide, and key measures are required to reduce the risks posed by antibiotic resistance genes that occur in the environment. These measures include the identification of critical points of control, the development of reliable surveillance and risk assessment procedures, and the implementation of technological solutions that can prevent environmental contamination with antibiotic resistant bacteria and genes. In this Opinion article, we discuss the main knowledge gaps, the future research needs and the policy and management options that should be prioritized to tackle antibiotic resistance in the environment. PMID:25817583

  8. Antibiotic research and development: business as usual?

    PubMed

    Harbarth, S; Theuretzbacher, U; Hackett, J

    2015-01-01

    The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents. PMID:25673635

  9. Antibiotic research and development: business as usual?

    PubMed

    Harbarth, S; Theuretzbacher, U; Hackett, J

    2015-01-01

    The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents.

  10. Design of dual action antibiotics as an approach to search for new promising drugs

    NASA Astrophysics Data System (ADS)

    Tevyashova, A. N.; Olsufyeva, E. N.; Preobrazhenskaya, M. N.

    2015-01-01

    The review is devoted to the latest achievements in the design of dual action antibiotics — heterodimeric (chimeric) structures based on antibacterial agents of different classes (fluoroquinolones, anthracyclines, oxazolidines, macrolides and so on). Covalent binding can make the pharmacokinetic characteristics of these molecules more predictable and improve the penetration of each component into the cell. Consequently, not only does the drug efficacy increase owing to inhibition of two targets but also the resistance to one or both antibiotics can be overcome. The theoretical grounds of elaboration, design principles and methods for the synthesis of dual action antibiotics are considered. The structures are classified according to the type of covalent spacer (cleavable or not) connecting the moieties of two agents. Dual action antibiotics with a spacer that can be cleaved in a living cell are considered as dual action prodrugs. Data on the biological action of heterodimeric compounds are presented and structure-activity relationships are analyzed. The bibliography includes 225 references.

  11. Pathophysiology of chronic bacterial osteomyelitis. Why do antibiotics fail so often?

    PubMed Central

    Ciampolini, J; Harding, K

    2000-01-01

    In this review the pathophysiology of chronic bacterial osteomyelitis is summarised, focusing on how bacteria succeed so often in overcoming both host defence mechanisms and antibiotic agents. Bacteria adhere to bone matrix and orthopaedic implants via receptors to fibronectin and to other structural proteins. They subsequently elude host defences and antibiotics by "hiding" intracellularly, by developing a slimy coat, or by acquiring a very slow metabolic rate. The presence of an orthopaedic implant also causes a local polymorphonuclear cell defect, with decreased ability to kill phagocytosed bacteria. Osteolysis is determined locally by the interaction of bacterial surface components with immune system cells and subsequent cytokine production. The increasing development of antibiotic resistance by Staphylococcus aureus and S epidermidis will probably make conservative treatment even less successful than it is now. A close interaction between orthopaedic surgeons and physicians, with combined medical and operative treatment, is to be commended.


Keywords: osteomyelitis; joint replacement infection; antibiotics; osteolysis PMID:10908375

  12. Nanocarriers for antibiotics: a promising solution to treat intracellular bacterial infections.

    PubMed

    Abed, Nadia; Couvreur, Patrick

    2014-06-01

    In the field of antibiotherapy, intracellular infections remain difficult to eradicate mainly due to the poor intracellular penetration of most of the commonly used antibiotics. Bacteria have quickly understood that their intracellular localisation allows them to be protected from the host immune system, but also from the action of antimicrobial agents. In addition, in most cases pathogens nestle in professional phagocytic cells, and can even use them as a 'Trojan horse' to induce a secondary site of infection thereby causing persistent or recurrent infections. Thus, new strategies had to be considered in order to counteract these problems. Amongst them, nanocarriers loaded with antibiotics represent a promising approach. Nowadays, it is possible to encapsulate, incorporate or even conjugate biologically active molecules into different families of nanocarriers such as liposomes or nanoparticles in order to deliver antibiotics intracellularly and hence to treat infections. This review gives an overview of the variety of nanocarriers developed to deliver antibiotics directly into infected cells.

  13. Pharmacokinetics and pharmacodynamics of antibiotics in biofilm infections of Pseudomonas aeruginosa in vitro and in vivo.

    PubMed

    Hengzhuang, Wang; Høiby, Niels; Ciofu, Oana

    2014-01-01

    Although progress on biofilm research has been obtained during the past decades, the treatment of biofilm infections with antibiotics remains a riddle. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of an antimicrobial agent provide important information helping to establish an efficient dosing regimen and to minimize the development of antimicrobial tolerance and resistance in biofilm infections. Unfortunately, most previous PK/PD studies of antibiotics have been done on planktonic cells, and extrapolation of the results on biofilms is problematic as bacterial biofilms differ from planktonic grown cells in the growth rate, gene expression, and metabolism. Here, we set up several protocols for the studies of PK/PD of antibiotics in biofilm infections of P. aeruginosa in vitro and in vivo. It should be underlined that none of the protocols in biofilms have yet been certificated for clinical use or proved useful for guidance of antibiotic therapy.

  14. Antibiotic stewardship: a call for action by the urologic community.

    PubMed

    Wagenlehner, Florian M E; Bartoletti, Ricardo; Cek, Mete; Grabe, Magnus; Kahlmeter, Gunnar; Pickard, Robert; Bjerklund-Johansen, Truls E

    2013-09-01

    Increasing antibiotic resistance and lack of new antibiotics in the near future calls for a variety of coordinated strategies called "Antibiotic stewardship", to improve antibiotic use with the goal of enhancing patient health outcomes and reducing emergence of resistance to antibiotics.

  15. Effects of temperature and antibiotics on persistence of antibiotic-resistant bacteria and antibiotic resistance genes in poultry litter

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The effect of low, residual concentrations of antibiotics in manure and other environmental matrices is not well understood. It has been hypothesized that antibiotic concentrations below clinical MIC (minimal inhibitory concentrations) are still capable of selecting for resistance. The objective of ...

  16. Identification of Acinetobacter baumannii serum-associated antibiotic efflux pump inhibitors.

    PubMed

    Blanchard, Catlyn; Barnett, Pamela; Perlmutter, Jessamyn; Dunman, Paul M

    2014-11-01

    Adaptive antibiotic resistance is a newly described phenomenon by which Acinetobacter baumannii induces efflux pump activity in response to host-associated environmental cues that may, in part, account for antibiotic treatment failures against clinically defined susceptible strains. To that end, during adaptation to growth in human serum, the organism induces approximately 22 putative efflux-associated genes and displays efflux-mediated minocycline tolerance at antibiotic concentrations corresponding to patient serum levels. Here, we show that in addition to minocycline, growth in human serum elicits A. baumannii efflux-mediated tolerance to the antibiotics ciprofloxacin, meropenem, tetracycline, and tigecycline. Moreover, using a whole-cell high-throughput screen and secondary assays, we identified novel serum-associated antibiotic efflux inhibitors that potentiated the activities of antibiotics toward serum-grown A. baumannii. Two compounds, Acinetobacter baumannii efflux pump inhibitor 1 (ABEPI1) [(E)-4-((4-chlorobenzylidene)amino)benezenesulfonamide] and ABEPI2 [N-tert-butyl-2-(1-tert-butyltetrazol-5-yl)sulfanylacetamide], were shown to lead to minocycline accumulation within A. baumannii during serum growth and inhibit the efflux potential of the organism. While both compounds also inhibited the antibiotic efflux properties of the bacterial pathogen Pseudomonas aeruginosa, they did not display significant cytotoxicity toward human cells or mammalian Ca(2+) channel inhibitory effects, suggesting that ABEPI1 and ABEPI2 represent promising structural scaffolds for the development of new classes of bacterial antibiotic efflux pump inhibitors that can be used to potentiate the activities of current and future antibiotics for the therapeutic intervention of Gram-negative bacterial infections.

  17. Bacteriophages as potential treatment option for antibiotic resistant bacteria.

    PubMed

    Bragg, Robert; van der Westhuizen, Wouter; Lee, Ji-Yun; Coetsee, Elke; Boucher, Charlotte

    2014-01-01

    The world is facing an ever-increasing problem with antibiotic resistant bacteria and we are rapidly heading for a post-antibiotic era. There is an urgent need to investigate alterative treatment options while there are still a few antibiotics left. Bacteriophages are viruses that specifically target bacteria. Before the development of antibiotics, some efforts were made to use bacteriophages as a treatment option, but most of this research stopped soon after the discovery of antibiotics. There are two different replication options which bacteriophages employ. These are the lytic and lysogenic life cycles. Both these life cycles have potential as treatment options. There are various advantages and disadvantages to the use of bacteriophages as treatment options. The main advantage is the specificity of bacteriophages and treatments can be designed to specifically target pathogenic bacteria while not negatively affecting the normal microbiota. There are various advantages to this. However, the high level of specificity also creates potential problems, the main being the requirement of highly specific diagnostic procedures. Another potential problem with phage therapy includes the development of immunity and limitations with the registration of phage therapy options. The latter is driving research toward the expression of phage genes which break the bacterial cell wall, which could then be used as a treatment option. Various aspects of phage therapy have been investigated in studies undertaken by our research group. We have investigated specificity of phages to various avian pathogenic E. coli isolates. Furthermore, the exciting NanoSAM technology has been employed to investigate bacteriophage replication and aspects of this will be discussed. PMID:24619620

  18. Bacteriophages as potential treatment option for antibiotic resistant bacteria.

    PubMed

    Bragg, Robert; van der Westhuizen, Wouter; Lee, Ji-Yun; Coetsee, Elke; Boucher, Charlotte

    2014-01-01

    The world is facing an ever-increasing problem with antibiotic resistant bacteria and we are rapidly heading for a post-antibiotic era. There is an urgent need to investigate alterative treatment options while there are still a few antibiotics left. Bacteriophages are viruses that specifically target bacteria. Before the development of antibiotics, some efforts were made to use bacteriophages as a treatment option, but most of this research stopped soon after the discovery of antibiotics. There are two different replication options which bacteriophages employ. These are the lytic and lysogenic life cycles. Both these life cycles have potential as treatment options. There are various advantages and disadvantages to the use of bacteriophages as treatment options. The main advantage is the specificity of bacteriophages and treatments can be designed to specifically target pathogenic bacteria while not negatively affecting the normal microbiota. There are various advantages to this. However, the high level of specificity also creates potential problems, the main being the requirement of highly specific diagnostic procedures. Another potential problem with phage therapy includes the development of immunity and limitations with the registration of phage therapy options. The latter is driving research toward the expression of phage genes which break the bacterial cell wall, which could then be used as a treatment option. Various aspects of phage therapy have been investigated in studies undertaken by our research group. We have investigated specificity of phages to various avian pathogenic E. coli isolates. Furthermore, the exciting NanoSAM technology has been employed to investigate bacteriophage replication and aspects of this will be discussed.

  19. An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance.

    PubMed

    Abed, Nadia; Saïd-Hassane, Fatouma; Zouhiri, Fatima; Mougin, Julie; Nicolas, Valérie; Desmaële, Didier; Gref, Ruxandra; Couvreur, Patrick

    2015-01-01

    The "Golden era" of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55-63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells.

  20. An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance

    PubMed Central

    Abed, Nadia; Saïd-Hassane, Fatouma; Zouhiri, Fatima; Mougin, Julie; Nicolas, Valérie; Desmaële, Didier; Gref, Ruxandra; Couvreur, Patrick

    2015-01-01

    The “Golden era” of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55–63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells. PMID:26311631

  1. A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment.

    PubMed

    Pienaar, Elsje; Cilfone, Nicholas A; Lin, Philana Ling; Dartois, Véronique; Mattila, Joshua T; Butler, J Russell; Flynn, JoAnne L; Kirschner, Denise E; Linderman, Jennifer J

    2015-02-21

    While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. Here we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non-permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. Finally, we find that on an individual granuloma basis, pre-treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome.

  2. Overcoming drug resistance with alginate oligosaccharides able to potentiate the action of selected antibiotics.

    PubMed

    Khan, Saira; Tøndervik, Anne; Sletta, Håvard; Klinkenberg, Geir; Emanuel, Charlotte; Onsøyen, Edvar; Myrvold, Rolf; Howe, Robin A; Walsh, Timothy R; Hill, Katja E; Thomas, David W

    2012-10-01

    The uncontrolled, often inappropriate use of antibiotics has resulted in the increasing prevalence of antibiotic-resistant pathogens, with major cost implications for both United States and European health care systems. We describe the utilization of a low-molecular-weight oligosaccharide nanomedicine (OligoG), based on the biopolymer alginate, which is able to perturb multidrug-resistant (MDR) bacteria by modulating biofilm formation and persistence and reducing resistance to antibiotic treatment, as evident using conventional and robotic MIC screening and microscopic analyses of biofilm structure. OligoG increased (up to 512-fold) the efficacy of conventional antibiotics against important MDR pathogens, including Pseudomonas, Acinetobacter, and Burkholderia spp., appearing to be effective with several classes of antibiotic (i.e., macrolides, β-lactams, and tetracyclines). Using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM), increasing concentrations (2%, 6%, and 10%) of alginate oligomer were shown to have a direct effect on the quality of the biofilms produced and on the health of the cells within that biofilm. Biofilm growth was visibly weakened in the presence of 10% OligoG, as seen by decreased biomass and increased intercellular spaces, with the bacterial cells themselves becoming distorted and uneven due to apparently damaged cell membranes. This report demonstrates the feasibility of reducing the tolerance of wound biofilms to antibiotics with the use of specific alginate preparations.

  3. Status Report from the Scientific Panel on Antibiotic Use in Dermatology of the American Acne and Rosacea Society: Part 1: Antibiotic Prescribing Patterns, Sources of Antibiotic Exposure, Antibiotic Consumption and Emergence of Antibiotic Resistance, Impact of Alterations in Antibiotic Prescribing, and Clinical Sequelae of Antibiotic Use.

    PubMed

    Del Rosso, James Q; Webster, Guy F; Rosen, Ted; Thiboutot, Diane; Leyden, James J; Gallo, Richard; Walker, Clay; Zhanel, George; Eichenfield, Lawrence

    2016-04-01

    Oral and topical antibiotics are commonly prescribed in dermatologie practice, often for noninfectious disorders, such as acne vulgaris and rosacea. Concerns related to antibiotic exposure from both medical and nonmedical sources require that clinicians consider in each case why and how antibiotics are being used and to make appropriate adjustments to limit antibiotic exposure whenever possible. This first article of a three-part series discusses prescribing patterns in dermatology, provides an overview of sources of antibiotic exposure, reviews the relative correlations between the magnitude of antibiotic consumption and emergence of antibiotic resistance patterns, evaluates the impact of alterations in antibiotic prescribing, and discusses the potential relevance and clinical sequelae of antibiotic use, with emphasis on how antibiotics are used in dermatology. PMID:27462384

  4. Antibiotic 'Report Card' Drills Guidelines into Dentists

    MedlinePlus

    ... appropriate. Overuse of the drugs can contribute to antibiotic resistance. In this study, Jan Clarkson of the University of Dundee in Scotland and colleagues analyzed data from the U.K. National Health ... antibiotics. These dentists were randomly assigned either to receive ...

  5. Repairing the broken market for antibiotic innovation.

    PubMed

    Outterson, Kevin; Powers, John H; Daniel, Gregory W; McClellan, Mark B

    2015-02-01

    Multidrug-resistant bacterial diseases pose serious and growing threats to human health. While innovation is important to all areas of health research, it is uniquely important in antibiotics. Resistance destroys the fruit of prior research, making it necessary to constantly innovate to avoid falling back into a pre-antibiotic era. But investment is declining in antibiotics, driven by competition from older antibiotics, the cost and uncertainty of the development process, and limited reimbursement incentives. Good public health practices curb inappropriate antibiotic use, making return on investment challenging in payment systems based on sales volume. We assess the impact of recent initiatives to improve antibiotic innovation, reflecting experience with all sixty-seven new molecular entity antibiotics approved by the Food and Drug Administration since 1980. Our analysis incorporates data and insights derived from several multistakeholder initiatives under way involving governments and the private sector on both sides of the Atlantic. We propose three specific reforms that could revitalize innovations that protect public health, while promoting long-term sustainability: increased incentives for antibiotic research and development, surveillance, and stewardship; greater targeting of incentives to high-priority public health needs, including reimbursement that is delinked from volume of drug use; and enhanced global collaboration, including a global treaty.

  6. Antibiotic resistance: a physicist’s view

    PubMed Central

    Allen, Rosalind; Waclaw, Bartłomiej

    2016-01-01

    The problem of antibiotic resistance poses challenges across many disciplines. One such challenge is to understand the fundamental science of how antibiotics work, and how resistance to them can emerge. This is an area where physicists can make important contributions. Here, we highlight cases where this is already happening, and suggest directions for further physics involvement in antimicrobial research. PMID:27510596

  7. Antibiotic-Resistant Bacteria: There is Hope.

    ERIC Educational Resources Information Center

    Offner, Susan

    1998-01-01

    Argues that reduction in the use of antibiotics would enable antibiotic-sensitive bacteria to flourish. Presents an activity designed to show students how a small, seemingly unimportant difference in doubling time can, over a period of time, make an enormous difference in population size. (DDR)

  8. Inhaled antibiotics in mechanically ventilated patients.

    PubMed

    Michalopoulos, A S; Falagas, M E

    2014-02-01

    During the last decade, inhaled antibiotics, especially colistin, has been widely used worldwide as a therapeutic option, supplementary to conventional intravenous antibiotics, for the treatment of multidrug-resistant (MDR) Gram-negative nosocomial and ventilator-associated pneumonia (VAP). Antimicrobial aerosols are commonly used in mechanically ventilated patients with VAP, although information regarding their efficacy and optimal technique of administration has been limited. Recent studies showed that the administration of inhaled antibiotics in addition to systemic antibiotics provided encouraging results associated with low toxicity for the management of VAP mainly due to MDR Gram negative bacteria. Although the theory behind aerosolized administration of antibiotics seems to be sound, there are limited data available to support the routine use of this modality since very few randomized controlled trials (RCTs) have still examined the efficacy of this approach in patients with VAP. Additionally, this route of antibiotic delivery has not been approved until now neither by the FDA nor by the European Medicines Agency (EMEA) in patients with VAP. However, since the problem of VAP due to MDR bacteria has been increased worldwide RCTs are urgently needed in order to prove the safety, efficiency and efficacy of inhaled antimicrobial agents administered alone or in conjunction with parenteral antibiotics for the management of VAP in critically ill patients. Indeed, more data are needed to establish the appropriate role of inhaled antibiotics for the treatment of VAP.

  9. [Modification of antibiotic resistance in microbial symbiosis].

    PubMed

    Aznabaeva, L M; Usviatsov, B Ia; Bukharin, O V

    2010-01-01

    In antibiotic therapy it is necessary to use drugs active against the pathogen in its association with the host normal microflora. The aim of the study was to investigate modification of antibiotic resistance under conditions of the pathogen association with the representatives of the host normal microflora and to develop the microbiological criteria for determining effectiveness of antibacterials. Modification of microbial antibiotic resistance was investigated in 408 associations. Various changes in the antibiotic resistance of the strains were revealed: synergism, antagonism and indifference. On the basis of the results it was concluded that in the choice of the antibiotic active against Staphylococcus aureus and Streptococcus pyogenes the preference should be given to oxacillin, gentamicin and levomycetin, since the resistance of the pathogens to these antibiotics under the association conditions did not increase, which could contribute to their destruction, whereas the resistance of the normoflora increased or did not change, which was important for its retention in the biocenosis. The data on changeability of the antibiotic resistance of the microbial strains under the association conditions made it possible to develop microbiological criteria for determining effectiveness of antibiotics in the treatment of inflammatory diseases of microbial etiology (RF Patent No. 2231554). PMID:21033469

  10. Antibiotic resistance: a physicist’s view

    NASA Astrophysics Data System (ADS)

    Allen, Rosalind; Waclaw, Bartłomiej

    2016-08-01

    The problem of antibiotic resistance poses challenges across many disciplines. One such challenge is to understand the fundamental science of how antibiotics work, and how resistance to them can emerge. This is an area where physicists can make important contributions. Here, we highlight cases where this is already happening, and suggest directions for further physics involvement in antimicrobial research.

  11. Topical and oral antibiotics for acne vulgaris.

    PubMed

    Del Rosso, James Q

    2016-06-01

    Antibiotics, both oral and topical, have been an integral component of the management of acne vulgaris (AV) for approximately 6 decades. Originally thought to be effective for AV due to their ability to inhibit proliferation of Propionibacterium acnes, it is now believed that at least some antibiotics also exert anti-inflammatory effects that provide additional therapeutic benefit. To add, an increase in strains of P acnes and other exposed bacteria that are less sensitive to antibiotics used to treat AV have emerged, with resistance directly correlated geographically with the magnitude of antibiotic use. Although antibiotics still remain part of the therapeutic armamentarium for AV treatment, current recommendations support the following when used to treat AV: 1) monotherapy use should be avoided; 2) use benzoyl peroxide concomitantly to reduce emergence of resistant P acnes strains; 3) oral antibiotics should be used in combination with a topical regimen for moderate-to-severe inflammatory AV; and 4) use oral antibiotics over a limited duration to achieve control of inflammatory AV with an exit plan in place to discontinue their use as soon as possible. When selecting an oral antibiotic to treat AV, potential adverse effects are important to consider.

  12. Repairing the broken market for antibiotic innovation.

    PubMed

    Outterson, Kevin; Powers, John H; Daniel, Gregory W; McClellan, Mark B

    2015-02-01

    Multidrug-resistant bacterial diseases pose serious and growing threats to human health. While innovation is important to all areas of health research, it is uniquely important in antibiotics. Resistance destroys the fruit of prior research, making it necessary to constantly innovate to avoid falling back into a pre-antibiotic era. But investment is declining in antibiotics, driven by competition from older antibiotics, the cost and uncertainty of the development process, and limited reimbursement incentives. Good public health practices curb inappropriate antibiotic use, making return on investment challenging in payment systems based on sales volume. We assess the impact of recent initiatives to improve antibiotic innovation, reflecting experience with all sixty-seven new molecular entity antibiotics approved by the Food and Drug Administration since 1980. Our analysis incorporates data and insights derived from several multistakeholder initiatives under way involving governments and the private sector on both sides of the Atlantic. We propose three specific reforms that could revitalize innovations that protect public health, while promoting long-term sustainability: increased incentives for antibiotic research and development, surveillance, and stewardship; greater targeting of incentives to high-priority public health needs, including reimbursement that is delinked from volume of drug use; and enhanced global collaboration, including a global treaty. PMID:25646108

  13. Transport and transformation of genetic information in the critical zone: The case of antibiotic resistance genes

    NASA Astrophysics Data System (ADS)

    Zhu, Y. G.

    2015-12-01

    In addition to material and energy flows, the dynamics and functions of the Earth's critical zone are intensively mediated by biological actions performed by diverse organisms. These biological actions are modulated by the expression of functional genes and their translation into enzymes that catalyze geochemical reactions, such as nutrient turnover and pollutant biodegradation. Although geobiology, as an interdisciplinary research area, is playing and vital role in linking biological and geochemical processes at different temporal and spatial scales, the distribution and transport of functional genes have rarely been investigated from the Earth's critical zone perspectives. To illustrate the framework of studies on the transport and transformation of genetic information in the critical zone, antibiotic resistance is taken as an example. Antibiotic resistance genes are considered as a group of emerging contaminants, and their emergence and spread within the critical zone on one hand are induced by anthropogenic activities, and on other hand are threatening human health worldwide. The transport and transformation of antibiotic resistance genes are controlled by both horizontal gene transfer between bacterial cells and the movement of bacteria harboring antibiotic resistance genes. In this paper, the fate and behavior of antibiotic resistance genes will be discussed in the following aspects: 1) general overview of environmental antibiotic resistance; 2) high through quantification of the resistome in various environmental media; 3) pathways of resistance gene flow within the critical zone; and 4) potential strategies in mitigating antibiotic resistance, particularly from the critical zone perspectives.

  14. A role for the bacterial GATC methylome in antibiotic stress survival.

    PubMed

    Cohen, Nadia R; Ross, Christian A; Jain, Saloni; Shapiro, Rebecca S; Gutierrez, Arnaud; Belenky, Peter; Li, Hu; Collins, James J

    2016-05-01

    Antibiotic resistance is an increasingly serious public health threat. Understanding pathways allowing bacteria to survive antibiotic stress may unveil new therapeutic targets. We explore the role of the bacterial epigenome in antibiotic stress survival using classical genetic tools and single-molecule real-time sequencing to characterize genomic methylation kinetics. We find that Escherichia coli survival under antibiotic pressure is severely compromised without adenine methylation at GATC sites. Although the adenine methylome remains stable during drug stress, without GATC methylation, methyl-dependent mismatch repair (MMR) is deleterious and, fueled by the drug-induced error-prone polymerase Pol IV, overwhelms cells with toxic DNA breaks. In multiple E. coli strains, including pathogenic and drug-resistant clinical isolates, DNA adenine methyltransferase deficiency potentiates antibiotics from the β-lactam and quinolone classes. This work indicates that the GATC methylome provides structural support for bacterial survival during antibiotic stress and suggests targeting bacterial DNA methylation as a viable approach to enhancing antibiotic activity. PMID:26998690

  15. A role for the bacterial GATC methylome in antibiotic stress survival

    PubMed Central

    Cohen, Nadia R.; Ross, Christian A.; Jain, Saloni; Shapiro, Rebecca S.; Gutierrez, Arnaud; Belenky, Peter; Li, Hu; Collins, James J.

    2016-01-01

    Antibiotic resistance is an increasingly serious public health threat1. Understanding pathways allowing bacteria to survive antibiotic stress may unveil new therapeutic targets2–8. We explore the role of the bacterial epigenome in antibiotic stress survival using classical genetic tools and single-molecule real-time sequencing to characterize genomic methylation kinetics. We find that Escherichia coli survival under antibiotic pressure is severely compromised without adenine methylation at GATC sites. While the adenine methylome remains stable during drug stress, without GATC methylation, methyl-dependent mismatch repair (MMR) is deleterious, and fueled by the drug-induced error-prone polymerase PolIV, overwhelms cells with toxic DNA breaks. In multiple E. coli strains, including pathogenic and drug-resistant clinical isolates, DNA adenine methyltransferase deficiency potentiates antibiotics from the β-lactam and quinolone classes. This work indicates that the GATC methylome provides structural support for bacterial survival during antibiotics stress and suggests targeting bacterial DNA methylation as a viable approach to enhancing antibiotic activity. PMID:26998690

  16. Penetration barrier contributes to bacterial biofilm-associated resistance against only select antibiotics, and exhibits genus-, strain- and antibiotic-specific differences.

    PubMed

    Singh, Rachna; Sahore, Simmi; Kaur, Preetinder; Rani, Alka; Ray, Pallab

    2016-08-01

    Bacterial biofilms are implicated in a wide range of implant-based and chronic infections. These infections are often associated with adverse therapeutic outcomes, owing to the decreased antibiotic susceptibility of biofilms compared with their planktonic counterparts. This altered biofilm susceptibility has been attributed to multiple factors, including a reduced antibiotic penetration. Although several studies have addressed the role of penetration barrier in biofilm-associated drug resistance, it remains inconclusive. This study was done to elucidate antibiotic penetration through biofilms formed by Staphylococcus aureus, S. epidermidis, Escherichia coli and Klebsiella pneumoniae, using an agar disk diffusion assay. Penetration capacity of six antimicrobial drugs from different classes (β-lactams, aminoglycosides, tetracyclines, phenicols, fluoroquinolones and glycopeptides) through biofilms formed by standard strains and clinical isolates from catheter-related bloodstream infections (CRBSI) was elucidated by measuring their growth-inhibition zones in lawn cultures on Mueller-Hinton agar, following diffusion of an antibiotic from an overlying disk through their biofilm to the agar medium. Penetration of only select antimicrobials (vancomycin and chloramphenicol) was hindered through biofilms. There was considerable variation in biofilm-permeating capacity depending upon the genus, strain/CRBSI isolate and antibiotic tested. Furthermore, antibiotics failed to kill the biofilm cells independent of penetration, indicating that other factors contributed substantially to biofilm resistance.

  17. Penetration barrier contributes to bacterial biofilm-associated resistance against only select antibiotics, and exhibits genus-, strain- and antibiotic-specific differences.

    PubMed

    Singh, Rachna; Sahore, Simmi; Kaur, Preetinder; Rani, Alka; Ray, Pallab

    2016-08-01

    Bacterial biofilms are implicated in a wide range of implant-based and chronic infections. These infections are often associated with adverse therapeutic outcomes, owing to the decreased antibiotic susceptibility of biofilms compared with their planktonic counterparts. This altered biofilm susceptibility has been attributed to multiple factors, including a reduced antibiotic penetration. Although several studies have addressed the role of penetration barrier in biofilm-associated drug resistance, it remains inconclusive. This study was done to elucidate antibiotic penetration through biofilms formed by Staphylococcus aureus, S. epidermidis, Escherichia coli and Klebsiella pneumoniae, using an agar disk diffusion assay. Penetration capacity of six antimicrobial drugs from different classes (β-lactams, aminoglycosides, tetracyclines, phenicols, fluoroquinolones and glycopeptides) through biofilms formed by standard strains and clinical isolates from catheter-related bloodstream infections (CRBSI) was elucidated by measuring their growth-inhibition zones in lawn cultures on Mueller-Hinton agar, following diffusion of an antibiotic from an overlying disk through their biofilm to the agar medium. Penetration of only select antimicrobials (vancomycin and chloramphenicol) was hindered through biofilms. There was considerable variation in biofilm-permeating capacity depending upon the genus, strain/CRBSI isolate and antibiotic tested. Furthermore, antibiotics failed to kill the biofilm cells independent of penetration, indicating that other factors contributed substantially to biofilm resistance. PMID:27402781

  18. General principles of antibiotic resistance in bacteria.

    PubMed

    Martinez, Jose L

    2014-03-01

    Given the impact of antibiotic resistance on human health, its study is of great interest from a clinical view- point. In addition, antibiotic resistance is one of the few examples of evolution that can be studied in real time. Knowing the general principles involved in the acquisition of antibiotic resistance is therefore of interest to clinicians, evolutionary biologists and ecologists. The origin of antibiotic resistance genes now possessed by human pathogens can be traced back to environmental microorganisms. Consequently, a full understanding of the evolution of antibiotic resistance requires the study of natural environments as well as clinical ecosystems. Updated information on the evolutionary mechanisms behind resistance, indicates that ecological connectivity, founder effect and fitness costs are important bottle- necks that modulate the transfer of resistance from environmental microorganisms to pathogens. PMID:24847651

  19. Innovation of novel antibiotics: an economic perspective.

    PubMed

    McKellar, Michael R; Fendrick, A Mark

    2014-10-15

    Despite the public attention to antibiotic overuse and the specter of antimicrobial-resistant pathogens, current infections necessitate the use of antibiotics. Yet, patients and providers may not fully consider the societal cost associated with inappropriate antimicrobial use and subsequent resistance. Policies intended to limit use to minimize resistance must be balanced with the competing concern of underutilization. It is difficult to determine whether research and development incentives or reducing the costs of bringing new antibiotics through expedited review will be sufficient. Likely, the most effective method would be allowing higher prices for use deemed to be clinically appropriate. The ultimate policy goal is to ensure that antibiotics are used appropriately, with the right patients receiving the right medication at the right time, and that the world has a steady stream of future antibiotics to effectively treat the resistant organisms that will inevitably emerge.

  20. [Antipyocyanic antibiotic therapy. Principles and efficacy factors].

    PubMed

    Cohen, R

    2006-10-01

    Pseudomonas aeruginosa is among the bacterial species one of the most resistant "naturally" to antibiotics and one of which acquires most easily resistance to antibiotics. The major principle of the treatment of the infections due to P. aeruginosa is the use of antibiotic association to decrease the risk of emergence of resistant strains. Pharmacokinetic-pharmacodynamic parameters of antimicrobials with antipseudomonal activity are gaining importance as a mean of optimization of antibiotic therapy: tobramycin among the aminosides, ceftazidime among the beta-lactam antibiotics and ciprofloxacin among the quinolones have the best profile. The new mechanisms of pathogenicity or resistance (biofilm secretion, quorum sensing, hypermutator phenomenon) far from being opposed to the rules of prescription reinforce and complicate them.

  1. Using antibiotics responsibly: are we there yet?

    PubMed

    Dyar, Oliver James; Obua, Celestino; Chandy, Sujith; Xiao, Yonghong; Stålsby Lundborg, Cecilia; Pulcini, Céline

    2016-08-01

    Problems of antibiotic access and excess coexist in the world today and are compounded by rising rates of antibiotic resistance. We introduce two dimensions of responsibility to this context: responsible individual practices and a broad societal obligation centered on sustainability. Acting on these responsibilities requires recognizing the potential tensions between an individual optimum for antibiotic use and the societal optimum. We relate the tragedy of the commons metaphor to this situation to illustrate the complexity involved, and we draw on real-world experiences in Uganda, India, China and France. We conclude that we must form a global stewardship of antibiotics that can link access, innovation and conservation efforts across countries to ensure sustainable access to effective antibiotics for all who need them. PMID:27501941

  2. Using antibiotics responsibly: are we there yet?

    PubMed

    Dyar, Oliver James; Obua, Celestino; Chandy, Sujith; Xiao, Yonghong; Stålsby Lundborg, Cecilia; Pulcini, Céline

    2016-08-01

    Problems of antibiotic access and excess coexist in the world today and are compounded by rising rates of antibiotic resistance. We introduce two dimensions of responsibility to this context: responsible individual practices and a broad societal obligation centered on sustainability. Acting on these responsibilities requires recognizing the potential tensions between an individual optimum for antibiotic use and the societal optimum. We relate the tragedy of the commons metaphor to this situation to illustrate the complexity involved, and we draw on real-world experiences in Uganda, India, China and France. We conclude that we must form a global stewardship of antibiotics that can link access, innovation and conservation efforts across countries to ensure sustainable access to effective antibiotics for all who need them.

  3. [Duration of antibiotic therapy in bacterial meningitis].

    PubMed

    Pereira, P Ricardo; Borges, Fernando; Mansinho, Kamal

    2013-01-01

    The duration of antibiotic therapy in bacterial meningitis is a controversial issue. Antibiotic regimens have changed over time along with the criteria used to determine the ideal antibiotic therapy duration. The authors aim to make an historical overview on this matter and simultaneously add the evidence of recent studies, pointing out some issues in results interpretation, namely, their design and the associated demographic and epidemiological questions. Clinical assays on this subject, with statistically significant results, are quite recent. Most of the scientific knowledge has been acquired empirically through the times. The actual investigation paradigm, in what concerns to antibiotic therapy in bacterial meningitis, lays on the dichotomy: "short versus long duration regimens". Nevertheless, so far, the existing studies have not completely cleared this doubt. Thus, despite some evidence suggests that short duration antibiotic regimens are effective for some patients, in patients with severe disease presentations or with other morbidities its use may be questioned.

  4. Retapamulin: a newer topical antibiotic.

    PubMed

    Dhingra, D; Parakh, A; Ramachandran, S

    2013-01-01

    Impetigo is a common childhood skin infection. There are reports of increasing drug resistance to the currently used topical antibiotics including fusidic acid and mupirocin. Retapamulin is a newer topical agent of pleuromutilin class approved by the Food and Drug Administration for treatment of impetigo in children and has been recently made available in the Indian market. It has been demonstrated to have low potential for the development of antibacterial resistance and a high degree of potency against poly drug resistant Gram-positive bacteria found in skin infections including Staphylococcus aureus strains. The drug is safe owing to low systemic absorption and has only minimal side-effect of local irritation at the site of application. PMID:23793314

  5. A novel antibiotic-delivery system by using ovotransferrin as targeting molecule.

    PubMed

    Ibrahim, Hisham R; Tatsumoto, Sayuri; Ono, Hajime; Van Immerseel, Filip; Raspoet, Ruth; Miyata, Takeshi

    2015-01-23

    Synthetic antibiotics and antimicrobial agents, such as sulfonamide and triclosan (TCS), have provided new avenues in the treatment of bacterial infections, as they target lethal intracellular pathways. Sulfonamide antibiotics block synthesis of folic acid by inhibiting dihydrofolate reductase (DHFR) while TCS block fatty acid synthesis through inhibition of enoyl-ACP reductase (FabI). They are water-insoluble agents and high doses are toxic, limiting their therapeutic efficiency. In this study, an antibiotic drug-targeting strategy based on utilizing ovotransferrin (OTf) as a carrier to allow specific targeting of the drug to microbial or mammalian cells via the transferrin receptor (TfR) is explored, with potential to alleviate insolubility and toxicity problems. Complexation, through non-covalent interaction, with OTf turned sulfa antibiotics or TCS into completely soluble in aqueous solution. OTf complexes showed superior bactericidal activity against several bacterial strains compared to the activity of free agents. Strikingly, a multi-drug resistant Salmonella strain become susceptible to antibiotics-OTf complexes while a tolC-knockout mutant strain become susceptible to OTf and more sensitive to the complexes. The antibiotic bound to OTf was, thus exported through the multi-drug efflux pump TolC in Salmonella wild-type strain. Further, antibiotics-OTf complexes were able to efficiently kill intracellular pathogens after infecting human colon carcinoma cells (HCT-116). The results demonstrate, for the first time, that the TfR mediated endocytosis of OTf can be utilized to specifically target drugs directly to pathogens or intracellularly infected cells and highlights the potency of the antibiotic-OTf complex for the treatment of infectious diseases.

  6. A novel antibiotic-delivery system by using ovotransferrin as targeting molecule.

    PubMed

    Ibrahim, Hisham R; Tatsumoto, Sayuri; Ono, Hajime; Van Immerseel, Filip; Raspoet, Ruth; Miyata, Takeshi

    2015-01-23

    Synthetic antibiotics and antimicrobial agents, such as sulfonamide and triclosan (TCS), have provided new avenues in the treatment of bacterial infections, as they target lethal intracellular pathways. Sulfonamide antibiotics block synthesis of folic acid by inhibiting dihydrofolate reductase (DHFR) while TCS block fatty acid synthesis through inhibition of enoyl-ACP reductase (FabI). They are water-insoluble agents and high doses are toxic, limiting their therapeutic efficiency. In this study, an antibiotic drug-targeting strategy based on utilizing ovotransferrin (OTf) as a carrier to allow specific targeting of the drug to microbial or mammalian cells via the transferrin receptor (TfR) is explored, with potential to alleviate insolubility and toxicity problems. Complexation, through non-covalent interaction, with OTf turned sulfa antibiotics or TCS into completely soluble in aqueous solution. OTf complexes showed superior bactericidal activity against several bacterial strains compared to the activity of free agents. Strikingly, a multi-drug resistant Salmonella strain become susceptible to antibiotics-OTf complexes while a tolC-knockout mutant strain become susceptible to OTf and more sensitive to the complexes. The antibiotic bound to OTf was, thus exported through the multi-drug efflux pump TolC in Salmonella wild-type strain. Further, antibiotics-OTf complexes were able to efficiently kill intracellular pathogens after infecting human colon carcinoma cells (HCT-116). The results demonstrate, for the first time, that the TfR mediated endocytosis of OTf can be utilized to specifically target drugs directly to pathogens or intracellularly infected cells and highlights the potency of the antibiotic-OTf complex for the treatment of infectious diseases. PMID:25315410

  7. Antibiotics: When They Can and Can't Help

    MedlinePlus

    ... and most coughs and sore throats. What is "antibiotic resistance?" “Antibiotic resistance” and “bacterial resistance” are two ways of describing the same thing. Usually, antibiotics kill bacteria or stop them from growing. However, ...

  8. Antibiotic-Resistant Bacteria Detected in Sewage Spill

    MedlinePlus

    ... animals -- the more the antibiotic resistant organisms and antibiotic resistance genes can enter the environment and contribute to the spread of antibiotic resistance, especially for those drugs considered the 'last resort' ...

  9. Systems, not pills: The options market for antibiotics seeks to rejuvenate the antibiotic pipeline.

    PubMed

    Brogan, David M; Mossialos, Elias

    2016-02-01

    Over the past decade, there has been a growing recognition of the increasing growth of antibiotic resistant bacteria and a relative decline in the production of novel antibacterial therapies. The combination of these two forces poses a potentially grave threat to global health, in both developed and developing countries. Current market forces do not provide appropriate incentives to stimulate new antibiotic development, thus we propose a new incentive mechanism: the Options Market for Antibiotics. This mechanism, modelled on the principle of financial call options, allows payers to buy the right, in early stages of development, to purchase antibiotics at a discounted price if and when they ever make it to market approval. This paper demonstrates the effect of such a model on the expected Net Present Value of a typical antibacterial project. As part of an integrated strategy to confront the impending antibiotic crisis, the Options Market for Antibiotics may effectively stimulate corporate and public investment into antibiotic research and development. PMID:26808335

  10. Systems, not pills: The options market for antibiotics seeks to rejuvenate the antibiotic pipeline.

    PubMed

    Brogan, David M; Mossialos, Elias

    2016-02-01

    Over the past decade, there has been a growing recognition of the increasing growth of antibiotic resistant bacteria and a relative decline in the production of novel antibacterial therapies. The combination of these two forces poses a potentially grave threat to global health, in both developed and developing countries. Current market forces do not provide appropriate incentives to stimulate new antibiotic development, thus we propose a new incentive mechanism: the Options Market for Antibiotics. This mechanism, modelled on the principle of financial call options, allows payers to buy the right, in early stages of development, to purchase antibiotics at a discounted price if and when they ever make it to market approval. This paper demonstrates the effect of such a model on the expected Net Present Value of a typical antibacterial project. As part of an integrated strategy to confront the impending antibiotic crisis, the Options Market for Antibiotics may effectively stimulate corporate and public investment into antibiotic research and development.

  11. Immunomodulatory effects of macrolide antibiotics - part 1: biological mechanisms.

    PubMed

    Altenburg, J; de Graaff, C S; van der Werf, T S; Boersma, W G

    2011-01-01

    Macrolide antibiotics are well known for their antibacterial and anti-inflammatory properties. This article provides an overview of the biological mechanisms through which macrolides exert this 'double effect'. Their antibacterial effect consists of the inhibition of bacterial protein synthesis, impaired bacterial biofilm synthesis, and the attenuation of other bacterial virulence factors. Apart from these direct antimicrobial effects, macrolides are known for their modulating effect on many components of the human immune system. By influencing the production of cytokines, they have a dampening effect on the proinflammatory response. Furthermore, the majority of cells involved in the immune response are, in one way or another, influenced when macrolide antibiotics are administered. Having such an obvious effect on the various aspects of the immune system, macrolides seem to be exceptionally suited for the treatment of chronic inflammatory diseases.

  12. Antibiotic susceptibility of different lactic acid bacteria strains.

    PubMed

    Karapetkov, N; Georgieva, R; Rumyan, N; Karaivanova, E

    2011-12-01

    Five lactic acid bacteria (LAB) strains belonging to species Lactobacillus acidophilus, Lactobacillus helveticus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus delbrueckii subsp. lactis and Streptococcus thermophilus were tested for their susceptibility to 27 antibiotics. The minimum inhibitory concentrations of each antimicrobial were determined using a microdilution test. Among the strains a high susceptibility was detected for most of the cell-wall synthesis inhibitors (penicillins, cefoxitin and vancomycin) and resistance toward inhibitors of DNA synthesis (trimethoprim/sulfonamides and fluoroquinolones). Generally, the Lactobacillus strains were inhibited by antibiotics such as chloramphenicol, erythromycin and tetracycline at breakpoint levels lower or equal to the levels defined by the European Food Safety Authority. Despite the very similar profile of S. thermophilus LC201 to lactobacilli, the detection of resistance toward erythromycin necessitates the performance of additional tests in order to prove the absence of transferable resistance genes.

  13. Time lapse investigation of antibiotic susceptibility using a microfluidic linear gradient 3D culture device.

    PubMed

    Hou, Zining; An, Yu; Hjort, Karin; Hjort, Klas; Sandegren, Linus; Wu, Zhigang

    2014-09-01

    This study reports a novel approach to quantitatively investigate the antibacterial effect of antibiotics on bacteria using a three-dimensional microfluidic culture device. In particular, our approach is suitable for studying the pharmacodynamics effects of antibiotics on bacterial cells temporally and with a continuous range of concentrations in a single experiment. The responses of bacterial cells to a linear concentration gradient of antibiotics were observed using time-lapse photography, by encapsulating bacterial cells in an agarose-based gel located in a commercially available microfluidics chamber. This approach generates dynamic information with high resolution, in a single operation, e.g., growth curves and antibiotic pharmacodynamics, in a well-controlled environment. No pre-labelling of the cells is needed and therefore any bacterial sample can be tested in this setup. It also provides static information comparable to that of standard techniques for measuring minimum inhibitory concentration (MIC). Five antibiotics with different mechanisms were analysed against wild-type Escherichia coli, Staphylococcus aureus and Salmonella Typhimurium. The entire process, including data analysis, took 2.5-4 h and from the same analysis, high-resolution growth curves were obtained. As a proof of principle, a pharmacodynamic model of streptomycin against Salmonella Typhimurium was built based on the maximal effect model, which agreed well with the experimental results. Our approach has the potential to be a simple and flexible solution to study responding behaviours of microbial cells under different selection pressures both temporally and in a range of concentrations.

  14. Multi-bacteria multi-antibiotic testing using surface enhanced Raman spectroscopy (SERS) for urinary tract infection (UTI) diagnosis

    NASA Astrophysics Data System (ADS)

    Hadjigeorgiou, Katerina; Kastanos, Evdokia; Pitris, Costas

    2013-06-01

    The inappropriate use of antibiotics leads to antibiotic resistance, which is a major health care problem. The current method for determination of bacterial susceptibility to antibiotics requires overnight cultures. However most of the infections cannot wait for the results to receive treatment, so physicians administer general spectrum antibiotics. This results in ineffective treatments and aggravates the rising problem of antibiotic resistance. In this work, a rapid method for diagnosis and antibiogram for a bacterial infection was developed using Surface Enhanced Raman Spectroscopy (SERS) with silver nanoparticles. The advantages of this novel method include its rapidness and efficiency which will potentially allow doctors to prescribe the most appropriate antibiotic for an infection. SERS spectra of three species of gram negative bacteria, Escherichia coli, Proteus spp., and Klebsiella spp. were obtained after 0 and 4 hour exposure to the seven different antibiotics. Bacterial strains were diluted in order to reach the concentration of (2x105 cfu/ml), cells/ml which is equivalent to the minimum concentration found in urine samples from UTIs. Even though the concentration of bacteria was low, species classification was achieved with 94% accuracy using spectra obtained at 0 hours. Sensitivity or resistance to antibiotics was predicted with 81%-100% accuracy from spectra obtained after 4 hours of exposure to the different antibiotics. This technique can be applied directly to urine samples, and with the enhancement provided by SERS, this method has the potential to be developed into a rapid method for same day UTI diagnosis and antibiogram.

  15. Alterations in peptidoglycan of Neisseria gonorrhoeae induced by sub-MICs of beta-lactam antibiotics.

    PubMed Central

    Garcia-Bustos, J F; Dougherty, T J

    1987-01-01

    Exposure of Neisseria gonorrhoeae to sub-MICs of selected beta-lactam antibiotics caused distortion of normal cell morphology. Analysis of the peptidoglycan indicated that the cells were accumulating increased quantities of disaccharide pentapeptide in their cell walls. The O-acetylated form of the disaccharide pentapeptide was not detected among the major peaks. The correlation of antibiotic binding to gonococcal penicillin-binding protein 2 and accumulation of non-O-acetylated disaccharide pentapeptide suggested an explanation for the previously observed relationship of penicillin-binding protein 2 and O-acetylation of peptidoglycan. PMID:3105447

  16. Do antibiotics have environmental side-effects? Impact of synthetic antibiotics on biogeochemical processes.

    PubMed

    Roose-Amsaleg, Céline; Laverman, Anniet M

    2016-03-01

    Antibiotic use in the early 1900 vastly improved human health but at the same time started an arms race of antibiotic resistance. The widespread use of antibiotics has resulted in ubiquitous trace concentrations of many antibiotics in most environments. Little is known about the impact of these antibiotics on microbial processes or "non-target" organisms. This mini-review summarizes our knowledge of the effect of synthetically produced antibiotics on microorganisms involved in biogeochemical cycling. We found only 31 articles that dealt with the effects of antibiotics on such processes in soil, sediment, or freshwater. We compare the processes, antibiotics, concentration range, source, environment, and experimental approach of these studies. Examining the effects of antibiotics on biogeochemical processes should involve environmentally relevant concentrations (instead of therapeutic), chronic exposure (versus acute), and monitoring of the administered antibiotics. Furthermore, the lack of standardized tests hinders generalizations regarding the effects of antibiotics on biogeochemical processes. We investigated the effects of antibiotics on biogeochemical N cycling, specifically nitrification, denitrification, and anammox. We found that environmentally relevant concentrations of fluoroquinolones and sulfonamides could partially inhibit denitrification. So far, the only documented effects of antibiotic inhibitions were at therapeutic doses on anammox activities. The most studied and inhibited was nitrification (25-100 %) mainly at therapeutic doses and rarely environmentally relevant. We recommend that firm conclusions regarding inhibition of antibiotics at environmentally relevant concentrations remain difficult due to the lack of studies testing low concentrations at chronic exposure. There is thus a need to test the effects of these environmental concentrations on biogeochemical processes to further establish the possible effects on ecosystem functioning.

  17. Phenotypic and gene expression responses of E. coli to antibiotics during spaceflight

    NASA Astrophysics Data System (ADS)

    Zea, Luis

    Bacterial susceptibility to antibiotics has been shown in vitro to be reduced during spaceflight; however, the underlying mechanisms responsible for this outcome are not fully understood. In particular, it is not yet clear whether this observed response is due to increased drug resistance (a microbial defense response) or decreased drug efficacy (a microgravity biophysical mass transport effect). To gain insight into the differentiation between these two potential causes, an investigation was undertaken onboard the International Space Station (ISS) in 2014 termed Antibiotic Effectiveness in Space-1 (AES-1). For this purpose, E. coli was challenged with two antibiotics, Gentamicin Sulfate and Colistin Sulfate, at concentrations higher than those needed to inhibit growth on Earth. Phenotypic parameters (cell size, cell envelope thickness, population density and lag phase duration) and gene expression were compared between the spaceflight samples and ground controls cultured in varying levels of drug concentration. It was observed that flight samples proliferated in antibiotic concentrations that were inhibitory on Earth, growing on average to a 13-fold greater concentration than matched 1g controls. Furthermore, at the highest drug concentrations in space, E. coli cells were observed to aggregate into visible clusters. In spaceflight, cell size was significantly reduced, translating to a decrease in cell surface area to about one half of the ground controls. Smaller cell surface area can in turn proportionally reduce the rate of antibiotic molecules reaching the cell. Additionally, it was observed that genes --- in some cases more than 2000 --- were overexpressed in space with respect to ground controls. Up-regulated genes include poxB, which helps catabolize glucose into organic acids that alter acidity around and inside the cell, and the gadABC family genes, which confer resistance to extreme acid conditions. The next step is to characterize the mechanisms behind

  18. Antibiotics Before Removal of Percutaneously Inserted Central Venous Catheters Reduces Clinical Sepsis in Premature Infants

    PubMed Central

    Reynolds, Gail E.; Tierney, Sarah B.

    2015-01-01

    OBJECTIVES: Evaluate the incidence of postcatheter removal clinical sepsis when antibiotics were infused prior to the removal of percutaneously inserted central venous catheters (PICCs). METHODS: A retrospective chart review of premature neonates (n = 196) weighing ≤1250 g at birth with 218 PICC line removals in the presence or absence of antibiotics at a tertiary level neonatal intensive care unit (NICU) between January 1, 2010, and May 31, 2012. Charts were reviewed looking for the presence of clinical sepsis defined as a sepsis workup including white blood cell count, differential, C-reactive protein, blood and/or cerebral spinal fluid (CSF), and urine cultures along with at least 48 hours of antibiotic therapy given within 72 hours after removal of a PICC line. Antibiotics were considered present at line removal if given within 12 hours before catheter removal either electively or at completion of a planned course. RESULTS: When antibiotics were given within 12 hours before PICC line removal, only 2% of the line removal episodes (1/48) resulted in a neonate developing clinical sepsis versus 13% (21/165) when no antibiotics were given prior to removal (p = 0.03, Fisher's exact test). Despite the increased use of elective antibiotics with line removal, there was no increase in total antibiotic usage due to the overall decrease in episodes of clinical sepsis or changes in antibiogram susceptibility patterns. CONCLUSIONS: There was an 11% absolute decrease and a 6-fold relative decrease in postcatheter removal clinical sepsis events in premature neonates who received antibiotics prior to PICC line removal. PMID:26170772

  19. Overview: Global and Local Impact of Antibiotic Resistance.

    PubMed

    Watkins, Richard R; Bonomo, Robert A

    2016-06-01

    The rapid and ongoing spread of antibiotic resistance poses a serious threat to global public health. The indiscriminant use of antibiotics in agriculture and human medicine along with increasingly connected societies has fueled the distribution of antibiotic-resistant bacteria. These factors together have led to rising numbers of infections caused by multidrug-resistant and pan-resistant bacteria, with increases in morbidity and mortality. This article summarizes the trends in antibiotic resistance, discusses the impact of antibiotic resistance on society, and reviews the use of antibiotics in agriculture. Feasible ways to tackle antibiotic resistance to avert a post-antibiotic era are suggested.

  20. A microfluidic platform for rapid, stress-induced antibiotic susceptibility testing of Staphylococcus aureus

    PubMed Central

    Kalashnikov, Maxim; Lee, Jean C.; Campbell, Jennifer; Sharon, Andre; Sauer-Budge, Alexis F.

    2012-01-01

    The emergence and spread of bacterial resistance to ever increasing classes of antibiotics intensifies the need for fast phenotype-based clinical tests for determining antibiotic susceptibility. Standard susceptibility testing relies on the passive observation of bacterial growth inhibition in the presence of antibiotics. In this paper, we present a novel microfluidic platform for antibiotic susceptibility testing basedon stress-activation of biosynthetic pathways that are the primary targets of antibiotics. We chose Staphylococcus aureus as a model system due to its clinical importance, and we selected bacterial cell wall biosynthesis as the primary target of both stress and antibiotic. Enzymatic and mechanical stresses were used to damage the bacterial cell wall, and a β-lactam antibiotic interfered with the repair process, resulting in rapid cell death of strains that harbor no resistance mechanism. In contrast, resistant bacteria remained viable under the assay conditions. Bacteria, covalently-bound to the bottom of the microfluidic channel, were subjected to mechanical shear stress created by flowing culture media through the microfluidic channel and to enzymatic stress with sub-inhibitory concentrations of the bactericidal agent lysostaphin. Bacterial cell death was monitored via fluorescence using the Sytox Green dead cell stain, and rates of killing were measured for the bacterial samples in the presence and absence of oxacillin. Using model susceptible (Sanger 476) and resistant (MW2) S. aureus strains, a metric was established to separate susceptible and resistant staphylococci based on normalized fluorescence values after 60 minutes of exposure to stress and antibiotic. Because this groundbreaking approach is not based on standard methodology, it circumvents the need for minimum inhibitory concentration (MIC) measurements and long wait times. We demonstrate the successful development of a rapid microfluidic-based and stress-activated antibiotic

  1. Evolution of resistance to a last-resort antibiotic in Staphyloccocus aureus via bacterial competition

    PubMed Central

    Koch, Gudrun; Yepes, Ana; Förstner, Konrad U.; Wermser, Charlotte; Stengel, Stephanie T.; Modamio, Jennifer; Ohlsen, Knut; Foster, Kevin R.; Lopez, Daniel

    2014-01-01

    Summary Antibiotic resistance is a key medical concern, with antibiotic use likely being an important cause. However, here we describe an alternative route to clinically-relevant antibiotic resistance that occurs solely due to competitive interactions between bacterial cells. We consistently observe that isolates of Methicillin-resistant Staphylococcus aureus diversify spontaneously into two distinct, sequentially arising strains. The first evolved strain outgrows the parent strain via secretion of surfactants and a toxic bacteriocin. The second is resistant to the bacteriocin. Importantly, this second strain is also resistant to intermediate levels of vancomycin. This so-called VISA (vancomycin-intermediate S. aureus) phenotype is seen in many hard-to-treat clinical isolates. This strain diversification also occurs during in vivo infection in a mouse model, consistent with the fact that both coevolved phenotypes resemble strains commonly found in clinic. Our study shows how competition between coevolving bacterial strains can generate antibiotic resistance and recapitulate key clinical phenotypes. PMID:25171407

  2. Antimicrobial metallopolymers and their bioconjugates with conventional antibiotics against multidrug-resistant bacteria.

    PubMed

    Zhang, Jiuyang; Chen, Yung Pin; Miller, Kristen P; Ganewatta, Mitra S; Bam, Marpe; Yan, Yi; Nagarkatti, Mitzi; Decho, Alan W; Tang, Chuanbing

    2014-04-01

    Bacteria are now becoming more resistant to most conventional antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), a complex of multidrug-resistant Gram-positive bacterial strains, has proven especially problematic in both hospital and community settings by deactivating conventional β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, through various mechanisms, resulting in increased mortality rates and hospitalization costs. Here we introduce a class of charged metallopolymers that exhibit synergistic effects against MRSA by efficiently inhibiting activity of β-lactamase and effectively lysing bacterial cells. Various conventional β-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin, and cefazolin, are protected from β-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic cobaltocenium moieties. These discoveries could provide a new pathway for designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug-resistant bacteria and superbugs.

  3. A novel microbead-based microfluidic device for rapid bacterial identification and antibiotic susceptibility testing.

    PubMed

    He, J; Mu, X; Guo, Z; Hao, H; Zhang, C; Zhao, Z; Wang, Q

    2014-12-01

    Effective treatment of infectious diseases depends on the ability to rapidly identify the infecting bacteria and the use of sensitive antibiotics. The currently used identification assays usually take more than 72 h to perform and have a low sensitivity. Herein, we present a microbead-based microfluidic platform that is highly sensitive and rapid for bacterial detection and antibiotic sensitivity testing. The platform includes four units, one of which is used for bacterial identification and the other three are used for susceptibility testing. Our results showed that Escherichia coli O157 at a cell density range of 10(1)-10(5) CFU/μL could be detected within 30 min. Additionally, the effects of three antibiotics on E. coli O157 were evaluated within 4-8 h. Overall, this integrated microbead-based microdevice provides a sensitive, rapid, reliable, and highly effective platform for the identification of bacteria, as well as antibiotic sensitivity testing.

  4. Carbohydrate-Based Antibiotics: A New Approach to Tackling the Problem of Resistance.

    PubMed

    Ritter, Thomas K.; Wong, Chi-Huey

    2001-10-01

    Recent interest in the problem of antibiotic resistance has led to the identification of new targets and strategies for antibiotic discovery. Among these efforts, the development of small molecules as antibiotics to target carbohydrate receptors or carbohydrate-modifying enzymes represents a new direction. This review covers recent work in this regard and discusses the impact of each strategy on the development of drug resistance. Particularly interesting targets include unique cell-surface carbohydrates, the transglycosylase involved in peptidoglycan biosynthesis, and bacterial RNA. With a greater understanding of the genome of different bacteria as well as advances in functional genomics and proteomics, we can expect the discovery of a variety of targets for the development of novel antibiotics.

  5. "Practical knowledge" and perceptions of antibiotics and antibiotic resistance among drugsellers in Tanzanian private drugstores

    PubMed Central

    2010-01-01

    Background Studies indicate that antibiotics are sold against regulation and without prescription in private drugstores in rural Tanzania. The objective of the study was to explore and describe antibiotics sale and dispensing practices and link it to drugseller knowledge and perceptions of antibiotics and antibiotic resistance. Methods Exit customers of private drugstores in eight districts were interviewed about the drugstore encounter and drugs bought. Drugsellers filled in a questionnaire with closed- and open-ended questions about antibiotics and resistance. Data were analyzed using mixed quantitative and qualitative methods. Results Of 350 interviewed exit customers, 24% had bought antibiotics. Thirty percent had seen a health worker before coming and almost all of these had a prescription. Antibiotics were dispensed mainly for cough, stomachache, genital complaints and diarrhea but not for malaria or headache. Dispensed drugs were assessed as relevant for the symptoms or disease presented in 83% of all cases and 51% for antibiotics specifically. Non-prescribed drugs were assessed as more relevant than the prescribed. The knowledge level of the drugseller was ranked as high or very high by 75% of the respondents. Seventy-five drugsellers from three districts participated. Seventy-nine percent stated that diseases caused by bacteria can be treated with antibiotics but 24% of these also said that antibiotics can be used for treating viral disease. Most (85%) said that STI can be treated with antibiotics while 1% said the same about headache, 4% general weakness and 3% 'all diseases'. Seventy-two percent had heard of antibiotic resistance. When describing what an antibiotic is, the respondents used six different kinds of keywords. Descriptions of what antibiotic resistance is and how it occurs were quite rational from a biomedical point of view with some exceptions. They gave rise to five categories and one theme: Perceiving antibiotic resistance based on

  6. Review of Cellular Changes in the Cochlea Due to Aminoglycoside Antibiotics

    ERIC Educational Resources Information Center

    Ding, Dalian; Salvi, Richard

    2005-01-01

    Over the past two decades, considerable progress has been made in understanding the mechanisms underlying aminoglycoside ototoxicity. Aminoglycoside damage progresses from cochlear base to apex and from outer to inner hair cells. Aminoglycoside antibiotics enter hair cells at the apical pole and are taken up into lysosomes and mitochondria.…

  7. Lysozyme as an alternative to growth promoting antibiotics in swine production

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lysozyme is a naturally occurring enzyme found in bodily secretions such as tears, saliva, and milk. It functions as an antimicrobial agent by cleaving the peptidoglycan component of bacterial cell walls, which leads to cell death. Antibiotics are also antimicrobials and have been fed at subtherape...

  8. Emergence of antibiotic-resistant extremophiles (AREs).

    PubMed

    Gabani, Prashant; Prakash, Dhan; Singh, Om V

    2012-09-01

    Excessive use of antibiotics in recent years has produced bacteria that are resistant to a wide array of antibiotics. Several genetic and non-genetic elements allow microorganisms to adapt and thrive under harsh environmental conditions such as lethal doses of antibiotics. We attempt to classify these microorganisms as antibiotic-resistant extremophiles (AREs). AREs develop strategies to gain greater resistance to antibiotics via accumulation of multiple genes or plasmids that harbor genes for multiple drug resistance (MDR). In addition to their altered expression of multiple genes, AREs also survive by producing enzymes such as penicillinase that inactivate antibiotics. It is of interest to identify the underlying molecular mechanisms by which the AREs are able to survive in the presence of wide arrays of high-dosage antibiotics. Technologically, "omics"-based approaches such as genomics have revealed a wide array of genes differentially expressed in AREs. Proteomics studies with 2DE, MALDI-TOF, and MS/MS have identified specific proteins, enzymes, and pumps that function in the adaptation mechanisms of AREs. This article discusses the molecular mechanisms by which microorganisms develop into AREs and how "omics" approaches can identify the genetic elements of these adaptation mechanisms. These objectives will assist the development of strategies and potential therapeutics to treat outbreaks of pathogenic microorganisms in the future.

  9. Molecular Regulation of Antibiotic Biosynthesis in Streptomyces

    PubMed Central

    Liu, Gang; Chandra, Govind; Niu, Guoqing

    2013-01-01

    SUMMARY Streptomycetes are the most abundant source of antibiotics. Typically, each species produces several antibiotics, with the profile being species specific. Streptomyces coelicolor, the model species, produces at least five different antibiotics. We review the regulation of antibiotic biosynthesis in S. coelicolor and other, nonmodel streptomycetes in the light of recent studies. The biosynthesis of each antibiotic is specified by a large gene cluster, usually including regulatory genes (cluster-situated regulators [CSRs]). These are the main point of connection with a plethora of generally conserved regulatory systems that monitor the organism's physiology, developmental state, population density, and environment to determine the onset and level of production of each antibiotic. Some CSRs may also be sensitive to the levels of different kinds of ligands, including products of the pathway itself, products of other antibiotic pathways in the same organism, and specialized regulatory small molecules such as gamma-butyrolactones. These interactions can result in self-reinforcing feed-forward circuitry and complex cross talk between pathways. The physiological signals and regulatory mechanisms may be of practical importance for the activation of the many cryptic secondary metabolic gene cluster pathways revealed by recent sequencing of numerous Streptomyces genomes. PMID:23471619

  10. Fungal treatment for the removal of antibiotics and antibiotic resistance genes in veterinary hospital wastewater.

    PubMed

    Lucas, D; Badia-Fabregat, M; Vicent, T; Caminal, G; Rodríguez-Mozaz, S; Balcázar, J L; Barceló, D

    2016-06-01

    The emergence and spread of antibiotic resistance represents one of the most important public health concerns and has been linked to the widespread use of antibiotics in veterinary and human medicine. The overall elimination of antibiotics in conventional wastewater treatment plants is quite low; therefore, residual amounts of these compounds are continuously discharged to receiving surface waters, which may promote the emergence of antibiotic resistance. In this study, the ability of a fungal treatment as an alternative wastewater treatment for the elimination of forty-seven antibiotics belonging to seven different groups (β-lactams, fluoroquinolones, macrolides, metronidazoles, sulfonamides, tetracyclines, and trimethoprim) was evaluated. 77% of antibiotics were removed after the fungal treatment, which is higher than removal obtained in conventional treatment plants. Moreover, the effect of fungal treatment on the removal of some antibiotic resistance genes (ARGs) was evaluated. The fungal treatment was also efficient in removing ARGs, such as ermB (resistance to macrolides), tetW (resistance to tetracyclines), blaTEM (resistance to β-lactams), sulI (resistance to sulfonamides) and qnrS (reduced susceptibility to fluoroquinolones). However, it was not possible to establish a clear link between concentrations of antibiotics and corresponding ARGs in wastewater, which leads to the conclusion that there are other factors that should be taken into consideration besides the antibiotic concentrations that reach aquatic ecosystems in order to explain the emergence and spread of antibiotic resistance. PMID:26991378

  11. Antibiotic surgical prophylaxis increases nasal carriage of antibiotic-resistant staphylococci.

    PubMed

    McMurray, Claire L; Hardy, Katherine J; Verlander, Neville Q; Hawkey, Peter M

    2015-12-01

    Staphylococci are a significant cause of hospital-acquired infection. Nasal carriage of Staphylococcus aureus is an important risk factor for infection in surgical patients and coagulase-negative staphylococci (CNS) are a major cause of prosthetic joint infections. The impact that antibiotic surgical prophylaxis has on the nasal carriage of staphylococci has not been studied. Daily nasal swabs were taken from 63 patients who received antibiotic surgical prophylaxis and 16 patients who received no antibiotics. Total aerobic bacterial count, S. aureus and CNS were enumerated by culture from nasal swabs. Representative isolates were typed by staphylococcal interspersed repeat units (SIRU) typing and PFGE, and MICs to nine antibiotics were determined. After antibiotic administration, there was a reduction in S. aureus counts (median - 2.3 log(10)c.f.u. ml(- 1)) in 64.0 % of S. aureus carriers, compared with only a 0.89 log(10)c.f.u. ml(- 1) reduction in 75.0 % of S. aureus carriers who did not receive antibiotics. A greater increase in the nasal carriage rate of meticillin-resistant CNS was observed after antibiotic surgical prophylaxis compared with hospitalization alone, with increases of 16.4 and 4.6 %, respectively. Antibiotic-resistant S. epidermidis carriage rate increased by 16.6 % after antibiotic administration compared with 7.5 % with hospitalization alone. Antibiotic surgical prophylaxis impacts the nasal carriage of both S. aureus and CNS.

  12. Fungal treatment for the removal of antibiotics and antibiotic resistance genes in veterinary hospital wastewater.

    PubMed

    Lucas, D; Badia-Fabregat, M; Vicent, T; Caminal, G; Rodríguez-Mozaz, S; Balcázar, J L; Barceló, D

    2016-06-01

    The emergence and spread of antibiotic resistance represents one of the most important public health concerns and has been linked to the widespread use of antibiotics in veterinary and human medicine. The overall elimination of antibiotics in conventional wastewater treatment plants is quite low; therefore, residual amounts of these compounds are continuously discharged to receiving surface waters, which may promote the emergence of antibiotic resistance. In this study, the ability of a fungal treatment as an alternative wastewater treatment for the elimination of forty-seven antibiotics belonging to seven different groups (β-lactams, fluoroquinolones, macrolides, metronidazoles, sulfonamides, tetracyclines, and trimethoprim) was evaluated. 77% of antibiotics were removed after the fungal treatment, which is higher than removal obtained in conventional treatment plants. Moreover, the effect of fungal treatment on the removal of some antibiotic resistance genes (ARGs) was evaluated. The fungal treatment was also efficient in removing ARGs, such as ermB (resistance to macrolides), tetW (resistance to tetracyclines), blaTEM (resistance to β-lactams), sulI (resistance to sulfonamides) and qnrS (reduced susceptibility to fluoroquinolones). However, it was not possible to establish a clear link between concentrations of antibiotics and corresponding ARGs in wastewater, which leads to the conclusion that there are other factors that should be taken into consideration besides the antibiotic concentrations that reach aquatic ecosystems in order to explain the emergence and spread of antibiotic resistance.

  13. Environmental dissemination of antibiotic resistance genes and correlation to anthropogenic contamination with antibiotics

    PubMed Central

    Berglund, Björn

    2015-01-01

    Antibiotic resistance is a growing problem which threatens modern healthcare globally. Resistance has traditionally been viewed as a clinical problem, but recently non-clinical environments have been highlighted as an important factor in the dissemination of antibiotic resistance genes (ARGs). Horizontal gene transfer (HGT) events are likely to be common in aquatic environments; integrons in particular are well suited for mediating environmental dissemination of ARGs. A growing body of evidence suggests that ARGs are ubiquitous in natural environments. Particularly, elevated levels of ARGs and integrons in aquatic environments are correlated to proximity to anthropogenic activities. The source of this increase is likely to be routine discharge of antibiotics and resistance genes, for example, via wastewater or run-off from livestock facilities and agriculture. While very high levels of antibiotic contamination are likely to select for resistant bacteria directly, the role of sub-inhibitory concentrations of antibiotics in environmental antibiotic resistance dissemination remains unclear. In vitro studies have shown that low levels of antibiotics can select for resistant mutants and also facilitate HGT, indicating the need for caution. Overall, it is becoming increasingly clear that the environment plays an important role in dissemination of antibiotic resistance; further studies are needed to elucidate key aspects of this process. Importantly, the levels of environmental antibiotic contamination at which resistant bacteria are selected for and HGT is facilitated at should be determined. This would enable better risk analyses and facilitate measures for preventing dissemination and development of antibiotic resistance in the environment. PMID:26356096

  14. Selective target inactivation rather than global metabolic dormancy causes antibiotic tolerance in uropathogens.

    PubMed

    Goneau, Lee W; Yeoh, Nigel S; MacDonald, Kyle W; Cadieux, Peter A; Burton, Jeremy P; Razvi, Hassan; Reid, Gregor

    2014-01-01

    Persister cells represent a multidrug-tolerant (MDT), physiologically distinct subpopulation of bacteria. The ability of these organisms to survive lethal antibiotic doses raises concern over their potential role in chronic disease, such as recurrent urinary tract infection (RUTI). Persistence is believed to be conveyed through global metabolic dormancy, which yields organisms unresponsive to external stimuli. However, recent studies have contested this stance. Here, various antibiotics that target different cellular processes were used to dissect the activity of transcription, translation, and peptidoglycan turnover in persister cells. Differential susceptibility patterns were found in type I and type II persisters, and responses differed between Staphylococcus saprophyticus and Escherichia coli uropathogens. Further, SOS-deficient strains were sensitized to ciprofloxacin, suggesting DNA gyrase activity in persisters and indicating the importance of active DNA repair systems for ciprofloxacin tolerance. These results indicate that global dormancy per se cannot sufficiently account for antibiotic tolerance. Rather, the activity of individual cellular processes dictates multidrug tolerance in an antibiotic-specific fashion. Furthermore, the susceptibility patterns of persisters depended on their mechanisms of onset, with subinhibitory antibiotic pretreatments selectively shutting down cognate targets and increasing the persister fraction against the same agent. Interestingly, antibiotics targeting transcription and translation enhanced persistence against multiple agents indirectly related to these processes. Conducting these assays with uropathogenic E. coli isolated from RUTI patients revealed an enriched persister fraction compared to organisms cleared with standard antibiotic therapy. This finding suggests that persister traits are either selected for during prolonged antibiotic treatment or initially contribute to therapy failure. PMID:24449771

  15. Antibiotics and the mechanics of cellular bulging in gram-negative bacteria

    NASA Astrophysics Data System (ADS)

    Daly, K.; Wingreen, Ned S.; Mukhopahyay, Ranjan

    2010-03-01

    For most bacteria, the cell wall, consisting of a cross-linked polymer network, is the primary stress-bearing structure. Due to the high osmotic pressure difference across the cell membrane, the presence of the cell wall is essential for cell stability. Recent experiments have addressed the effect of cell-wall defects induced by antibiotics such as vancomycin, and find that in Gram-negative bacteria, antibiotics can lead to pronounced bulging of the cell membrane and eventually to lysis. Here we address the mechanics of bulging and its relationship to cell-wall defects. We estimate the critical defect size for bulging and discuss the biological implications of our results. We also discuss the relevance of our physical model to blebbing and vesiculation in eukaryotic cells.

  16. Broad spectrum antibiotic compounds and use thereof

    DOEpatents

    Koglin, Alexander; Strieker, Matthias

    2016-07-05

    The discovery of a non-ribosomal peptide synthetase (NRPS) gene cluster in the genome of Clostridium thermocellum that produces a secondary metabolite that is assembled outside of the host membrane is described. Also described is the identification of homologous NRPS gene clusters from several additional microorganisms. The secondary metabolites produced by the NRPS gene clusters exhibit broad spectrum antibiotic activity. Thus, antibiotic compounds produced by the NRPS gene clusters, and analogs thereof, their use for inhibiting bacterial growth, and methods of making the antibiotic compounds are described.

  17. How Nature Morphs Peptide Scaffolds into Antibiotics

    PubMed Central

    Nolan, Elizabeth M.; Walsh, Christopher T.

    2010-01-01

    The conventional notion that peptides are poor candidates for orally available drugs because of protease-sensitive peptide bonds, intrinsic hydrophilicity, and ionic charges contrasts with the diversity of antibiotic natural products with peptide-based frameworks that are synthesized and utilized by Nature. Several of these antibiotics, including penicillin and vancomycin, are employed to treat bacterial infections in humans and have been best-selling therapeutics for decades. Others might provide new platforms for the design of novel therapeutics to combat emerging antibiotic-resistant bacterial pathogens. PMID:19058272

  18. Developing New Antibiotics with Combinatorial Biosynthesis

    NASA Astrophysics Data System (ADS)

    Pohl, Nicola L.

    2000-11-01

    Polyketide synthases (PKSs), a class of enzymes found in soil bacteria that produce antibiotics such as erythromycin, string together acetate units using basic organic reactions. The manipulation of the sequence of these reactions at the genetic level has resulted in an alteration of the corresponding chemical structure of the antibiotic produced by the bacteria. This process, called combinatorial biosynthesis, allows the generation of many presently unknown complex structures that can be tested for antibacterial activity, thereby contributing to the race against antibiotic-resistant infectious bacteria.

  19. Structure–function insights reveal the human ribosome as a cancer target for antibiotics

    PubMed Central

    Myasnikov, Alexander G.; Kundhavai Natchiar, S.; Nebout, Marielle; Hazemann, Isabelle; Imbert, Véronique; Khatter, Heena; Peyron, Jean-François; Klaholz, Bruno P.

    2016-01-01

    Many antibiotics in clinical use target the bacterial ribosome by interfering with the protein synthesis machinery. However, targeting the human ribosome in the case of protein synthesis deregulations such as in highly proliferating cancer cells has not been investigated at the molecular level up to now. Here we report the structure of the human 80S ribosome with a eukaryote-specific antibiotic and show its anti-proliferative effect on several cancer cell lines. The structure provides insights into the detailed interactions in a ligand-binding pocket of the human ribosome that are required for structure-assisted drug design. Furthermore, anti-proliferative dose response in leukaemic cells and interference with synthesis of c-myc and mcl-1 short-lived protein markers reveals specificity of a series of eukaryote-specific antibiotics towards cytosolic rather than mitochondrial ribosomes, uncovering the human ribosome as a promising cancer target. PMID:27665925

  20. Syphilis: antibiotic treatment and resistance.

    PubMed

    Stamm, L V

    2015-06-01

    Syphilis is a chronic, multi-stage infectious disease that is usually transmitted sexually by contact with an active lesion of a partner or congenitally from an infected pregnant woman to her fetus. Although syphilis is still endemic in many developing countries, it has re-emerged in several developed countries. The resurgence of syphilis is a major concern to global public health, particularly since the lesions of early syphilis increase the risk of acquisition and transmission of infection with human immunodeficiency virus (HIV). Because there is no vaccine to prevent syphilis, control is mainly dependent on the identification and treatment of infected individuals and their contacts with penicillin G, the first-line drug for all stages of syphilis. The emergence of clinically significant azithromycin resistance in Treponema pallidum subsp. pallidum, the syphilis agent, has resulted in treatment failures, thus precluding the routine use of this second-line drug. Information is presented here on the diagnosis and recommended antibiotic treatment of syphilis and the challenge of macrolide-resistant T. pallidum.