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Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies.

ABSTRACT: Antibiotic tolerance, or the ability of bacteria to survive antibiotic treatment in the absence of genetic resistance, has been linked to chronic and recurrent infections. Tolerant cells are often characterized by a low metabolic state, against which most clinically used antibiotics are ineffective. Here, we show that tolerance readily evolves against antibiotics that are strongly dependent on bacterial metabolism, but does not arise against antibiotics whose efficacy is only minimally affected by metabolic state. We identify a mechanism of tolerance evolution in E. coli involving deletion of the sodium-proton antiporter gene nhaA, which results in downregulated metabolism and upregulated stress responses. Additionally, we find that cycling of antibiotics with different metabolic dependencies interrupts evolution of tolerance in vitro, increasing the lifetime of treatment efficacy. Our work highlights the potential for limiting the occurrence and extent of tolerance by accounting for antibiotic dependencies on bacterial metabolism.

SUBMITTER: Zheng EJ

PROVIDER: S-EPMC9085803 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies.

Zheng Erica J EJ Andrews Ian W IW Grote Alexandra T AT Manson Abigail L AL Alcantar Miguel A MA Earl Ashlee M AM Collins James J JJ

Nature communications 20220509 1

Antibiotic tolerance, or the ability of bacteria to survive antibiotic treatment in the absence of genetic resistance, has been linked to chronic and recurrent infections. Tolerant cells are often characterized by a low metabolic state, against which most clinically used antibiotics are ineffective. Here, we show that tolerance readily evolves against antibiotics that are strongly dependent on bacterial metabolism, but does not arise against antibiotics whose efficacy is only minimally affected ...[more]

PMID: 35534481

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Project description:The global crisis of antimicrobial resistance poses a major threat to human health, underscoring the urgency of developing new antibacterial strategies. Antimicrobial peptides (AMPs) are promising alternatives to antibiotic therapy, yet potential microbial resistance is of great concern. Resistance is often accompanied by fitness costs, which may in turn influence the spread of drug-resistant bacteria and their susceptibility to other antimicrobial agents. Herein, we investigate the evolutionary trajectory of bacterial resistance to antibiotics and AMPs in Escherichia coli, and evaluate the fitness costs and collateral sensitivity of drug-resistant strains. We reveal that E. coli develops resistance to antibiotics, particularly ciprofloxacin and kanamycin, at a notably faster rate than to AMPs. Moreover, antibiotic-evolved strains exhibit slightly higher fitness costs than AMP-evolved bacteria, primarily manifested in reduced bacterial growth and swimming motility. Notably, we demonstrate that trimethoprim-resistant E. coli, with mutations in thyA gene, displays enhanced susceptibility to pexiganan, as evidenced by both in vitro and in vivo studies. Overall, our findings shed new insights for the clinical deployment of AMPs and propose innovative therapeutic strategies for combating antibiotic-resistant bacterial infections.IMPORTANCEThe global spread of antimicrobial resistance necessitates the development of innovative anti-infective strategies. Antimicrobial peptides (AMPs) represent promising alternatives in the post-antibiotic era. By monitoring the evolutionary trajectory of bacterial resistance to eight antibiotics and ten AMPs in Escherichia coli, we demonstrate that E. coli exhibits slower emergence of resistance against AMPs compared with antibiotics. Additionally, these antibiotic-resistant strains incur significant fitness costs, particularly in bacterial growth and motility. Most importantly, we find that some antibiotic-resistant strains show collateral sensitivity to specific AMPs in both in vitro and animal infection models, which is conducive to accelerating the development of AMP-based antibacterial treatment.

Dataset Information

Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies.

Publications

Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies.

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