Adaptation Through Lifestyle Switching Sculpts the Fitness Landscape of Evolving Populations: Implications for the Selection of Drug-Resistant Bacteria at Low Drug Pressures

Matange, Nishad; Hegde, Sushmitha; Bodkhe, Swapnil

doi:10.1534/genetics.119.301834

Cited by 12 publications

(27 citation statements)

References 72 publications

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“…Mounting evidence now suggests that the evolutionary trajectories that sub-MIC selection can follow are different from those seen under conditions of high drug concentrations. In at least two different cases, sub-MIC drug pressures were also shown to select for very high-level drug resistance (2,3). The results obtained in the present study mirror these results conceptually, as Lon deficiency enhanced the level of trimethoprim resistance (i.e., the drug MIC) for several of the mutants tested.…”

Section: Discussionsupporting

confidence: 83%

“…Further, the fitness advantage conferred by Lon deficiency at sub-MICs of trimethoprim is relevant in the context of selection under conditions of low drug pressure. Sub-MICs of antibiotics are likely to be encountered by bacteria in natural habitats such as soil and water and are known to select for clinically relevant drug resistance (2,3,43). Mounting evidence now suggests that the evolutionary trajectories that sub-MIC selection can follow are different from those seen under conditions of high drug concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…Though conceptually straightforward, this idea is rendered complex in practice since the fitness of drug-resistant strains is influenced by several cell-intrinsic and extrinsic factors. For instance, recent studies have demonstrated that the outcomes of selection for resistance can be influenced by environmental factors such as drug concentration (1)(2)(3)(4), drug exposure duration (2,5), and drug interactions (6,7). Among cell-intrinsic factors, genetic background is an important determinant of how drug resistance evolution proceeds.…”

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confidence: 99%

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Highly Contingent Phenotypes of Lon Protease Deficiency in Escherichia coli upon Antibiotic Challenge

Matange

2020

J Bacteriol

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Evolutionary trajectories and mutational landscapes of drug-resistant bacteria are influenced by cell-intrinsic and extrinsic factors. In this study, I demonstrated that loss of the Lon protease altered susceptibility of Escherichia coli to trimethoprim and that these effects were strongly contingent on the drug concentration and genetic background. Lon, an AAA+ ATPase, is a bacterial master regulator protease involved in cytokinesis, suppression of transposition events, and clearance of misfolded proteins. I show that Lon deficiency enhances intrinsic drug tolerance at sub-MIC levels of trimethoprim. As a result, loss of Lon, though disadvantageous under drug-free conditions, has a selective advantage at low concentrations of trimethoprim. At high drug concentrations, however, Lon deficiency is detrimental for E. coli. I show that the former is explained by suppression of drug efflux by Lon, while the latter can be attributed to SulA-dependent hyperfilamentation. On the other hand, deletion of lon in a trimethoprim-resistant mutant E. coli strain (harboring the Trp30Gly dihydrofolate reductase [DHFR] allele) directly potentiates resistance by enhancing the in vivo stability of mutant DHFR. Using extensive mutational analysis at 3 hot spots of resistance, I show that many resistance-conferring mutations render DHFR prone to proteolysis. This trade-off between gaining resistance and losing in vivo stability limits the number of mutations in DHFR that can confer trimethoprim resistance. Loss of Lon expands the mutational capacity for acquisition of trimethoprim resistance. This paper identifies the multipronged action of Lon in trimethoprim resistance in E. coli and provides mechanistic insight into how genetic backgrounds and drug concentrations may alter the potential for antimicrobial resistance evolution. IMPORTANCE Understanding the evolutionary dynamics of antimicrobial resistance is vital to curb its emergence and spread. Being fundamentally similar to natural selection, the fitness of resistant mutants is a key parameter to consider in the evolutionary dynamics of antimicrobial resistance (AMR). Various intrinsic and extrinsic factors modulate the fitness of resistant bacteria. This study demonstrated that Lon, a bacterial master regulator protease, influences drug tolerance and resistance. Lon is a key regulator of several fundamental processes in bacteria, including cytokinesis. I demonstrated that Lon deficiency produces highly contingent phenotypes in E. coli challenged with trimethoprim and can expand the mutational repertoire available to E. coli to evolve resistance. This multipronged influence of Lon on drug resistance provides an illustrative instance of how master regulators shape the response of bacteria to antibiotics.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Highly Contingent Phenotypes of Lon Protease Deficiency in Escherichia coli upon Antibiotic Challenge

Matange

2020

J Bacteriol

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“…Inhibitory Concentration-50 (IC50): IC50 of trimethoprim was determined using a broth dilution assay as described in Matange et al (2019) [40]and Matange et a. (2018) [33].…”

Section: Antibiotic Sensitivitymentioning

confidence: 99%

Adaptation and Compensation in a Bacterial Gene Regulatory Network Evolving Under Antibiotic Selection

Patel

Matange

2021

Preprint

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Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that early evolutionary response of Escherichia coli to the antibiotic trimethoprim involves de-repression of PhoPQ signalling, a Mg2+-sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that de-repression of PhoPQ confers trimethoprim-tolerance to E. coli by hitherto unrecognized transcriptional up-regulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in mgrB precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing and mutation re-construction, we show that populations of E. coli challenged with trimethoprim are faced with the evolutionary "choice" of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ de-repression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by strength of antibiotic selection, such that high pressures favour resistance, while low pressures favour cost-compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.

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“…Previous work revealed that inactivation of the regulator fimE leads cells to shift their lifestyle from planktonic to pellicle-like growth in broth cultures without reducing the growth rate (Matange et al, 2019;Stentebjerg-Olesen et al, 2000). Pellicle formation by fimE inactivation was also observed to be selected for in E. coli cells exposed to the antibiotic rifamycin and was found to improve resistance by increasing cell aggregation due to increased cell adhesion (Matange et al, 2019). It is therefore possible that a similar mechanism also improves 5FU and FUDR resistance and can therefore explain the frequent inactivation of fimE in our evolution experiments.…”

Section: Evolved Mutations Influence Multiple Resistance Mechanismsmentioning

confidence: 99%

Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host

Rosener

Sayin

Oluoch

et al. 2020

eLife

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Metabolism of host-targeted drugs by the microbiome can substantially impact host treatment success. However, since many host-targeted drugs inadvertently hamper microbiome growth, repeated drug administration can lead to microbiome evolutionary adaptation. We tested if evolved bacterial resistance against host-targeted drugs alters their drug metabolism and impacts host treatment success. We used a model system of C. elegans, its bacterial diet, and two fluoropyrimidine chemotherapies. Genetic screens revealed that most of loss-of-function resistance mutations in Escherichia coli also reduced drug toxicity in the host. We found that resistance rapidly emerged in E. coli under natural selection and converged to a handful of resistance mechanisms. Surprisingly, we discovered that nutrient availability during bacterial evolution dictated the dietary effect on the host – only bacteria evolving in nutrient-poor media reduced host drug toxicity. Our work suggests that bacteria can rapidly adapt to host-targeted drugs and by doing so may also impact the host.

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Adaptation Through Lifestyle Switching Sculpts the Fitness Landscape of Evolving Populations: Implications for the Selection of Drug-Resistant Bacteria at Low Drug Pressures

Cited by 12 publications

References 72 publications

Highly Contingent Phenotypes of Lon Protease Deficiency in Escherichia coli upon Antibiotic Challenge

Highly Contingent Phenotypes of Lon Protease Deficiency in Escherichia coli upon Antibiotic Challenge

Adaptation and Compensation in a Bacterial Gene Regulatory Network Evolving Under Antibiotic Selection

Evolved bacterial resistance against fluoropyrimidines can lower chemotherapy impact in the Caenorhabditis elegans host

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