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Systematic Investigation of Resistance Evolution to Common Antibiotics Reveals Conserved Collateral Responses across Common Human Pathogens.

ABSTRACT: As drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will be increasingly relied upon to treat infections and to lower the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism's collateral response to a wide variety of antibiotics. The results of these studies have been used to identify networks of drugs which can be used to drive resistance in a particular direction. However, little is known about the extent of evolutionary conservation of these responses across species. We sought to address this knowledge gap by performing a systematic resistance evolution study of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) under uniform growth conditions using five clinically relevant antibiotics with diverse modes of action. Evolved lineages were analyzed for collateral effects and the molecular mechanisms behind the observed phenotypes. Fourteen universal cross-resistance and two global collateral sensitivity relationships were found among the lineages. Genomic analyses revealed drug-dependent divergent and conserved evolutionary trajectories among the pathogens. Our findings suggest that collateral responses may be preserved across species. These findings may help extend the contribution of previous collateral network studies in the development of treatment strategies to address the problem of antibiotic resistance.

SUBMITTER: Rodriguez de Evgrafov MC

PROVIDER: S-EPMC7927859 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Antibiotic resistance in our pathogens is medicine's climate change: caused by human activity, and resulting in more extreme outcomes. Resistance emerges in microbial populations when antibiotics act on phenotypic variance within the population. This can arise from either genotypic diversity (resulting from a mutation or horizontal gene transfer), or from differences in gene expression due to environmental variation, referred to as adaptive resistance. Adaptive changes can increase fitness allowing bacteria to survive at higher concentrations of antibiotics. They can also decrease fitness, potentially leading to selection for antibiotic resistance at lower concentrations. There are opportunities for other environmental stressors to promote antibiotic resistance in ways that are hard to predict using conventional assays. Exploiting our previous observation that commonly used herbicides can increase or decrease the minimum inhibitory concentration (MIC) of different antibiotics, we provide the first comprehensive test of the hypothesis that the rate of antibiotic resistance evolution under specified conditions can increase, regardless of whether a herbicide increases or decreases the antibiotic MIC. Short term evolution experiments were used for various herbicide and antibiotic combinations. We found conditions where acquired resistance arises more frequently regardless of whether the exogenous non-antibiotic agent increased or decreased antibiotic effectiveness. This is attributed to the effect of the herbicide on either MIC or the minimum selective concentration (MSC) of a paired antibiotic. The MSC is the lowest concentration of antibiotic at which the fitness of individuals varies because of the antibiotic, and is lower than MIC. Our results suggest that additional environmental factors influencing competition between bacteria could enhance the ability of antibiotics to select antibiotic resistance. Our work demonstrates that bacteria may acquire antibiotic resistance in the environment at rates substantially faster than predicted from laboratory conditions.

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Systematic Investigation of Resistance Evolution to Common Antibiotics Reveals Conserved Collateral Responses across Common Human Pathogens.

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