A roadblock-and-kill model explains the dynamical response to the DNA-targeting antibiotic ciprofloxacin

Ojkic, Nikola; Lilja, Elin; Direito, S.; Dawson, Angela; Allen, Rosalind J.; Waclaw, Bartłomiej

doi:10.1101/791145

“…Another approach would be an experiment similar to that from figure 1, in which a mutagen such as UV irradiation creates a burst of mutants. Other signatures of phenotypic delay may be detected in experiments where the timing of antibiotic exposure, and of resistance evolution, can be precisely controlled, for example in turbidostat-like continuous culture devices [90].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic delay in the evolution of bacterial antibiotic resistance: mechanistic models and their implications

Carballo-Pacheco

¹

,

Nicholson

²

,

Lilja

³

et al. 2019

Preprint

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Phenotypic delay -the time delay between genetic mutation and expression of the corresponding phenotype -is generally neglected in evolutionary models, yet recent work suggests that it may be more common than previously assumed. Here, we use computer simulations and theory to investigate the significance of phenotypic delay for the evolution of bacterial resistance to antibiotics. We consider three mechanisms which could potentially cause phenotypic delay: effective polyploidy, dilution of antibiotic-sensitive molecules and accumulation of resistance-enhancing molecules. We find that the accumulation of resistant molecules is relevant only within a narrow parameter range, but both the dilution of sensitive molecules and effective polyploidy can cause phenotypic delay over a wide range of parameters. We further investigate whether these mechanisms could affect population survival under drug treatment and thereby explain observed discrepancies in mutation rates estimated by Luria-Delbrück fluctuation tests. While the effective polyploidy mechanism does not affect population survival, the dilution of sensitive molecules leads both to decreased probability of survival under drug treatment and underestimation of mutation rates in fluctuation tests. The dilution mechanism also changes the shape of the Luria-Delbrück distribution of mutant numbers, and we show that this modified distribution provides an improved fit to previously published experimental data. Author SummaryUnderstanding precisely how some bacteria survive exposure to antibiotics is a major research focus. Specific mutations in the bacterial genome are known to provide protection. However, it remains unclear how much time passes between a bacterium acquiring the genetic change and being able to tolerate antibiotics -termed the phenotypic delay -and what controls this delay. Here, using computer simulations and mathematical arguments we discuss three biologically plausible mechanisms of phenotypic delay. We investigate how each mechanism would affect the outcome of laboratory experiments often used to study the evolution of antibiotic resistance, and we highlight ¶These authors contributed equally to this work. *Corresponding authors: rosalind.allen@ed.ac.uk, bwaclaw@staffmail.ed.ac.uk 1 how the delay might be detected in such experiments. We also show that the existence of the delay could explain an observed discrepancy in the measurement of mutation rates, and demonstrate that one of our models provides a superior fit to experimental data. Our work exposes how molecular details at the intracellular level can have a direct effect on evolution at the population level.

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“…Yet another approach would be an experiment similar to the thought experiment from Fig 1, in which a mutagen such as UV irradiation creates a burst of mutants. Other signatures of phenotypic delay may be detected in experiments where the timing of antibiotic exposure, and of resistance evolution, can be precisely controlled, for example in turbidostat-like continuous culture devices [90].…”

Section: Experimental Tests For Phenotypic Delaymentioning

confidence: 99%

Phenotypic delay in the evolution of bacterial antibiotic resistance: Mechanistic models and their implications

Carballo-Pacheco

¹

,

Nicholson

²

,

Lilja

³

et al. 2020

Self Cite

View full text Add to dashboard Cite

Phenotypic delay-the time delay between genetic mutation and expression of the corresponding phenotype-is generally neglected in evolutionary models, yet recent work suggests that it may be more common than previously assumed. Here, we use computer simulations and theory to investigate the significance of phenotypic delay for the evolution of bacterial resistance to antibiotics. We consider three mechanisms which could potentially cause phenotypic delay: effective polyploidy, dilution of antibiotic-sensitive molecules and accumulation of resistance-enhancing molecules. We find that the accumulation of resistant molecules is relevant only within a narrow parameter range, but both the dilution of sensitive molecules and effective polyploidy can cause phenotypic delay over a wide range of parameters. We further investigate whether these mechanisms could affect population survival under drug treatment and thereby explain observed discrepancies in mutation rates estimated by Luria-Delbrü ck fluctuation tests. While the effective polyploidy mechanism does not affect population survival, the dilution of sensitive molecules leads both to decreased probability of survival under drug treatment and underestimation of mutation rates in fluctuation tests. The dilution mechanism also changes the shape of the Luria-Delbrü ck distribution of mutant numbers, and we show that this modified distribution provides an improved fit to previously published experimental data.

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Predicting trajectories and mechanisms of antibiotic resistance evolution

Pinheiro

¹

,

Warsi

²

,

Andersson

³

et al. 2020

Preprint

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Bacteria evolve resistance to antibiotics by a multitude of mechanisms. A central, yet unsolved question is how resistance evolution affects cell growth at different drug levels. Here we develop a fitness model that predicts growth rates of common resistance mutants from their effects on cell metabolism. We map metabolic effects of resistance mutations in drug-free environments and under drug challenge; the resulting fitness trade-off defines a Pareto surface of resistance evolution. We predict evolutionary trajectories of dosage-dependent growth rates and resistance levels, as well as the prevalent resistance mechanism depending on drug and nutrient levels. These predictions are confirmed by empirical growth curves and genomic data of E. coli populations. Our results show that resistance evolution, by coupling major metabolic pathways, is strongly intertwined with systems biology and ecology of microbial populations.

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A roadblock-and-kill model explains the dynamical response to the DNA-targeting antibiotic ciprofloxacin

Cited by 4 publications

References 66 publications

Phenotypic delay in the evolution of bacterial antibiotic resistance: mechanistic models and their implications

Phenotypic delay in the evolution of bacterial antibiotic resistance: mechanistic models and their implications

Phenotypic delay in the evolution of bacterial antibiotic resistance: Mechanistic models and their implications

Predicting trajectories and mechanisms of antibiotic resistance evolution

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