Restriction of Arginine Induces Antibiotic Tolerance in Staphylococcus aureus
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ABSTRACT:
ORGANISM(S): Staphylococcus aureus
PROVIDER: GSE267626 | GEO | 2024/07/10
REPOSITORIES: GEO
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Project description:Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics were examined using both quantitative proteomics and transposon sequencing. These screens indicated that arginine metabolism is involved in antibiotic tolerance within a biofilm and led to the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH, the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction was found to induce antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections.
2024-07-11 | PXD052440 | Pride
Project description:Tan2012 - Antibiotic Treatment, Inoculum Effect
The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies.
This model is described in the article:
The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.
Tan C, Phillip Smith R, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L.
Mol Syst Biol. 2012 Oct 9; 8:617
Abstract:
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.
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2024-09-02 | BIOMD0000000425 | BioModels
Project description:Staphylococcus aureus is a major human pathogen and resistant to numerous clinically used antibiotics. The first antibiotic developed for S. aureus infections was the nonribosomal petide secondary metabolite penicillin. We discovered cryptic nonribosomal peptide secondary metabolites, the aureusimines, made by S. aureus itself that are not antibiotics, but function as small molecule regulators of virulence factor expression. Using established rules and codes for nonribosomal peptide assembly we predicted these nonribosomal peptides, and used these predictions to identify them from S. aureus culture broths. Functional studies using global microarray and mouse bacteremia models established that the aureusimines control virulence factor expression and are necessary for productive infections. This is the first report of the aureusimines and has important implications for the treatment of drug resistant S. aureus. Targeting aureusimine synthesis may provide novel anti-infectives.
2010-07-01 | GSE21373 | GEO
Project description:Staphylococcus aureus is a major human pathogen and resistant to numerous clinically used antibiotics. The first antibiotic developed for S. aureus infections was the nonribosomal petide secondary metabolite penicillin. We discovered cryptic nonribosomal peptide secondary metabolites, the aureusimines, made by S. aureus itself that are not antibiotics, but function as small molecule regulators of virulence factor expression. Using established rules and codes for nonribosomal peptide assembly we predicted these nonribosomal peptides, and used these predictions to identify them from S. aureus culture broths. Functional studies using global microarray and mouse bacteremia models established that the aureusimines control virulence factor expression and are necessary for productive infections. This is the first report of the aureusimines and has important implications for the treatment of drug resistant S. aureus. Targeting aureusimine synthesis may provide novel anti-infectives. Commerically available S. aureus GeneChips (Affymetrix) were used to compare biological replicates of early and late exponential phase wild type (Newman) and aureusimine defective (ausA) organisms.
2010-07-30 | E-GEOD-21373 | biostudies-arrayexpress
Project description:Staphylococcus aureus and Pseudomonas aeruginosa are the most prevalent pathogens that colonize structurally abnormal airways such as those in Cystic Fibrosis (CF) and other chronic obstructive lung diseases. Although these bacteria seem to succeed one another, CF patients acquire coinciding P. aeruginosa and S. aureus pulmonary infections, being co-infection usually associated with decreased lung function and increased frequency of pulmonary exacerbations. In addition, P. aeruginosa and S. aureus pathogens adopt a biofilm mode of growth, which contributes to high tolerance to antibiotic treatment and the recalcitrant nature of these chronic coinfections, leading to significant patient morbidity and mortality. Interactions between P. aeruginosa and S. aureus have been widely studied and it is commonly admitted that P. aeruginosa outcompetes S. aureus, perhaps outcompeting S. aureus for limited nutrients or producing anti-staphylococcal compounds, having S. aureus a minimal contribution to the overall course of the infection. However, the molecular mechanisms behind these interactions are largely unknown. Herein, we decided to characterize the full transcriptome of these dual-species biofilms, to unveil important molecular interactions that can occur between these two bacterial species that are relevant for the pathogenesis of the entire consortia. Our data provide novel insights into the role of interspecies interactions in the pathogenesis of P. aeruginosa and S. aureus co-infections and will contribute to future studies by the research community.
2022-08-03 | GSE195909 | GEO
Project description:Isoquinolines (IQs) are natural substances with antibiotic potential. IQ-238 is a synthetic analog of the novel-type N,C-coupled naphtylisoquinoline (NIQ) alkaloid ancisheynine. Gene expression data, cytotoxicity measurements and metabolic modelling is combined to assess the effects of the N,C-coupled naphtylisoquinoline (NIQ) compound IQ-238 on Staphylococcus aureus and man as a potential lead for novel antibiotics. It possesses a high activity against staphylococci but has low cytotoxicity in human cell lines. Genome annotation identified missed enzymes (validated by PCR) in the primary (e.g. nucleotide) metabolism of staphylococci. Gene expression changed after cultivation with IQ-238. Metabolic modelling did yield the adaptations of all central enzymes, including those not affected by significant gene expression changes. The data show that IQ-238 interferes with the carbohydrate metabolism in staphylococci. The data suggest that IQ-238 is a promising lead for antibiotic therapy against S. aureus infections. HG001 WT strain exposed to GB-AP-238 in rich medium
2015-04-30 | E-GEOD-33832 | biostudies-arrayexpress
Project description:The human pathogenic bacterium Listeria monocytogenes was exposed to antibiotics both during clinical treatment and as a saprophyte. As one of the keys to successful treatment is continued antibiotic sensitivity, the purpose of this study was to determine if exposure to sublethal antibiotic concentrations would affect the bacterial physiology and potentially induce tolerance to antibiotics. Transcriptomic analyses demonstrated that each of four antibiotics caused a compound-specific gene expression pattern related to (the) mode-of-action of the particular antibiotic. All four antibiotics caused the same changes in expression of several metabolic genes indicating a shift from aerobic to anaerobic metabolism driven by the induction of lmo1634 and the repression of alsA and lmo1992. This shift in metabolism could be a survival strategy in response to antibiotics and is further supported by the observation that a Îlmo1634 mutant was more sensitive to bactericidal antibiotics. The monocin locus encoding a cryptic prophage was induced by co-trimoxazole and repressed by ampicillin and gentamicin. This expression pattern correlated with the observed antibiotic-dependent biofilm formation, indicating a role of monocin in antibiotic-induced biofilm formation and a ÎlmaDCBA mutant confirmed this correlation. Thus, sublethal concentrations of antibiotics caused metabolic and physiological changes indicating that the organism is preparing to withstand lethal concentrations of antibiotics. Investigation of mRNA and sRNA expression profiles of L. monocytogenes EGD cells exposed to sublethal concentrations of four different antibiotics i.e. ampicillin, tetracycline, gentamicin and co-trimoxazole for 3h.
2016-06-01 | E-GEOD-65558 | biostudies-arrayexpress
Project description:The human pathogenic bacterium Listeria monocytogenes was exposed to antibiotics both during clinical treatment and as a saprophyte. As one of the keys to successful treatment is continued antibiotic sensitivity, the purpose of this study was to determine if exposure to sublethal antibiotic concentrations would affect the bacterial physiology and potentially induce tolerance to antibiotics. Transcriptomic analyses demonstrated that each of four antibiotics caused a compound-specific gene expression pattern related to (the) mode-of-action of the particular antibiotic. All four antibiotics caused the same changes in expression of several metabolic genes indicating a shift from aerobic to anaerobic metabolism driven by the induction of lmo1634 and the repression of alsA and lmo1992. This shift in metabolism could be a survival strategy in response to antibiotics and is further supported by the observation that a Δlmo1634 mutant was more sensitive to bactericidal antibiotics. The monocin locus encoding a cryptic prophage was induced by co-trimoxazole and repressed by ampicillin and gentamicin. This expression pattern correlated with the observed antibiotic-dependent biofilm formation, indicating a role of monocin in antibiotic-induced biofilm formation and a ΔlmaDCBA mutant confirmed this correlation. Thus, sublethal concentrations of antibiotics caused metabolic and physiological changes indicating that the organism is preparing to withstand lethal concentrations of antibiotics.
2016-06-01 | GSE65558 | GEO
Project description:Kaiser2014 - Salmonella persistence after ciprofloxacin treatment
The model describes the bacterial tolerance to antibiotics. Using a mouse model for Salmonella diarrhea, the authors have found that bacterial persistence occurs in the presence of the antibiotic ciprofloxacin because Salmonella can exist in two different states. One, the fast-growing population that spreads in the host's tissues and the other, slow-growing "persister" population that hide out inside dendritic cells of the host's immune system and cannot be attacked by the antibiotics. However, this can be killed by adding agents that directly stimulate the host's immune defense.
This model is described in the article:
Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment.
Kaiser P, Regoes RR, Dolowschiak T, Wotzka SY, Lengefeld J, Slack E, Grant AJ, Ackermann M, Hardt WD.
PLoS Biol. 2014 Feb 18;12(2):e1001793.
Abstract:
In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%-20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103⁺CX₃CR1⁻CD11c⁺ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics.
This model is hosted on BioModels Database and identified
by: MODEL1312170001.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication for more information.
2024-09-02 | BIOMD0000000527 | BioModels
Project description:Staphylococcus aureus can cause severe invasive infections that require prolonged antibiotic treatment. Although S. aureus can easily acquire antibiotic resistance, even fully susceptible bacteria can persist and survive antibiotic therapy, thus complicating treatment. These so-called persisters are phenotypic variants of bacteria characterized by an arrested-growth phenotype that can tolerate high concentrations of chemotherapeutics and are associated with chronic and recurrent infections. Here, we show that S. aureus recovered directly from infection sites, displayed an increased bacterial lag-phase heterogeneity, forming more non-stable small colonies, indicating the presence of dormant bacteria. Infection modelling showed that host-mediated stress, including acidic pH, neutrophil exposure and murine abscesses, as well as antibiotic treatment, promoted formation of persisters both in vitro and in vivo. Proteomics and RNA-sequencing revealed molecular changes in bacteria in response to acidic stress leading to an overall more virulent population. However, after persister-enrichment, S. aureus displayed downregulation of pathways involved in virulence, cell division, and DNA replication, while ribosomal proteins, nucleotide-, and amino acid- metabolic pathways were upregulated, suggesting their requirement to fuel and maintain the persister phenotype. We demonstrate that decreased aconitase activity and ATP-levels as well as accumulation of insoluble proteins correlated with dormancy and growth reactivation cycles. Combination of antibiotics with retinoid derivatives, especially CD1530, significantly reduced both persisters and total bacterial load in a murine infection model. Our study provides an in-depth characterization of S. aureus persisters and shows that treatment failure due to antibiotic persistence could be addressed by using retinoid derivatives in combination with conventional antibiotics.
2021-09-09 | PXD018372 | Pride