Evolutionary paths to antibiotic resistance under dynamically sustained drug selection

Toprak, Erdal; Veres, Adrian; Michel, Jean Baptiste; Chait, Remy; Hartl, Daniel L.; Kishony, Roy

doi:10.1038/ng.1034

Cited by 670 publications

(837 citation statements)

References 48 publications

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“…A comparison with the literature lead us to believe that this result is probably not peculiar to our specific conditions, but rather it could be fairly general. While our system, in fact, exhibited substantial flexibility in evolutionary trajectories, this flexibility is similar to what is typically observed in many bacterial evolution experiments [51]: hard adaptive constraints are rarely observed at the nucleotide level [52], and even in the examples that reported the highest degree of molecular convergence, adaptation involved more than one loci and featured a considerable amount of intralocus diversity [53][54][55]. Therefore, given that mutational target sizes seem not strictly limited, we expect spectrum effects on evolvability to be modest at best in most cases.…”

Section: Discussionsupporting

confidence: 80%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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Genetic constraints can block many mutational pathways to optimal genotypes in real fitness landscapes, yet the extent to which this can limit evolution remains to be determined. Interestingly, mutator bacteria elevate only specific types of mutations, and therefore could be very sensitive to genetic constraints. Testing this possibility is not only clinically relevant, but can also inform about the general impact of genetic constraints in adaptation. Here, we evolved 576 populations of two mutator and one wild-type Escherichia coli to doubling concentrations of the antibiotic cefotaxime. All strains carried TEM-1, a b-lactamase enzyme well known by its low availability of mutational pathways. Crucially, one of the mutators does not elevate any of the relevant first-step mutations known to improve cefatoximase activity. Despite this, both mutators displayed a similar ability to evolve more than 1000-fold resistance. Initial adaptation proceeded in parallel through general multi-drug resistance mechanisms. High-level resistance, in contrast, was achieved through divergent paths; with the a priori inferior mutator exploiting alternative mutational pathways in PBP3, the target of the antibiotic. These results have implications for mutator management in clinical infections and, more generally, illustrate that limits to natural selection in real organisms are alleviated by the existence of multiple loci contributing to fitness.

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Section: Discussionsupporting

confidence: 80%

Bypass of genetic constraints during mutator evolution to antibiotic resistance

2015

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“…fitness landscapes | DHFR | drug resistance | protein stability | molten globule P redictive models of antibiotic resistance are key to developing novel antibacterial treatments (1)(2)(3)(4)(5)(6). Besides its practical importance, antibiotic escape presents a tractable general model of adaptive evolutionary dynamics that can provide insights into fundamental questions in evolution, such as the reproducibility and predictability of evolutionary trajectories (4,7,8) as well as the importance of epistasis and pleiotropy (5,7,9,10).…”

mentioning

confidence: 99%

“…However, mutations conferring resistance against trimethoprim (TMP) were largely limited to the target gene, namely the ORF and upstream region of folA, the gene encoding dihydrofolate reductase (DHFR) (1,5,11). DHFR is an essential core metabolic enzyme that converts dihydrofolate to tetrahydrofolate-a main source of carbon atoms in several key pathways.…”

mentioning

confidence: 99%

Biophysical principles predict fitness landscapes of drug resistance

Rodrigues

Bershtein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

146

263

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Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi. We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype–phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

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“…To explore this hypothesis, we evolved the same ancestral strain toward tolerance to heat, but in increments of 1°C every 50 generations (from 30°C up to 39°C). This evolutionary design resembles the "morbidostat" that was recently applied to evolution of drug resistance in bacteria (26). Curiously, under this regime an extra copy of chromosome III was not gained after 450 generations in any of the four repetitions (termed Gradual 1-4) of the experiment (Fig.…”

Section: Elimination Of the Extra Copy Of Chromosome III At Permissivementioning

confidence: 99%

Chromosomal duplication is a transient evolutionary solution to stress

Yona

Manor

Herbst

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

319

371

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Aneuploidy, an abnormal number of chromosomes, is a widespread phenomenon found in unicellulars such as yeast, as well as in plants and in mammalians, especially in cancer. Aneuploidy is a genomescale aberration that imposes a severe burden on the cell, yet under stressful conditions specific aneuploidies confer a selective advantage. This dual nature of aneuploidy raises the question of whether it can serve as a stable and sustainable evolutionary adaptation. To clarify this, we conducted a set of laboratory evolution experiments in yeast and followed the long-term dynamics of aneuploidy under diverse conditions. Here we show that chromosomal duplications are first acquired as a crude solution to stress, yet only as transient solutions that are eliminated and replaced by more efficient solutions obtained at the individual gene level. These transient dynamics of aneuploidy were repeatedly observed in our laboratory evolution experiments; chromosomal duplications gained under stress were eliminated not only when the stress was relieved, but even if it persisted. Furthermore, when stress was applied gradually rather than abruptly, alternative solutions appear to have emerged, but not aneuploidy. Our findings indicate that chromosomal duplication is a first evolutionary line of defense, that retains survivability under strong and abrupt selective pressures, yet it merely serves as a "quick fix," whereas more refined and sustainable solutions take over. Thus, in the perspective of genome evolution trajectory, aneuploidy is a useful yet short-lived intermediate that facilitates further adaptation.evolutionary dynamics | environmental stress | heat tolerance | pH tolerance

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Evolutionary paths to antibiotic resistance under dynamically sustained drug selection

Cited by 670 publications

References 48 publications

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Bypass of genetic constraints during mutator evolution to antibiotic resistance

Biophysical principles predict fitness landscapes of drug resistance

Chromosomal duplication is a transient evolutionary solution to stress

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