Evolution of Cost-Free Resistance under Fluctuating Drug Selection in Pseudomonas aeruginosa

Melnyk, Anita H.; McCloskey, Nicholas; Hinz, Aaron; Dettman, Jeremy R.; Kassen, Rees

doi:10.1128/msphere.00158-17

Cited by 54 publications

(39 citation statements)

References 61 publications

(68 reference statements)

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“…3B, Table S3; log 10 (MIC) * day interaction from model comparison: χ 2 = 0.2112, P = 0.6459). This result is consistent with the selection of second-site compensatory mutations that improve growth rate under drug-free conditions without compromising resistance (Gagneux et al 2006;Comas et al 2012;Wong et al 2012;Melnyk et al 2017) or the selective replacement of costly resistance mutations by independently-arising resistance mutations with lower costs. Irrespective of the underlying genetic causes of this weakened trade-off, the internal equilibrium frequency of resistant strains (i.e., resistance frequency when ω = 1) increases on average from ß59% at day 20 to ß87% by day 40 (Fig.…”

Section: Resultssupporting

confidence: 81%

“…; Melnyk et al. ) or the selective replacement of costly resistance mutations by independently‐arising resistance mutations with lower costs. Irrespective of the underlying genetic causes of this weakened trade‐off, the internal equilibrium frequency of resistant strains (i.e., resistance frequency when ω = 1) increases on average from ∼59% at day 20 to ∼87% by day 40 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Periodic delivery of a drug in time generates regular cycles of strong antibiotic selection followed by periods of relaxed selection when the drug is either metabolized, excreted, or not in use (Mackenzie and Gould 1993;Mouton and Vinks 1996). Intermittent dosing or ward-wide use generates fluctuating selection that leads to the evolution of broadly adapted resistant types with high fitness in both the presence and absence of drug (Melnyk et al 2017). Drug delivery may also be spatially variable across wards in a hospital or among compartments (tissues or organs) within a host, generating divergent selection that can lead to the emergence of a single resistant generalist or, if selection is sufficiently strong relative to dispersal (which can happen, e.g., through the movement of patients and staff between hospital wards), the coexistence of more narrowly adapted sensitive and resistant genotypes that trade-off drug resistance with growth rate in the absence of drug (Felsenstein 1976;Debarre et al 2009;Kassen 2014).…”

Section: Impact Summarymentioning

confidence: 99%

“…Empirical evidence bearing on these predictions remains sparse. Drug sanctuaries in time have been shown to select for cost-free, drug resistant genotypes (Melnyk et al 2017) while spatial gradients in drug delivery can lead to fairly rapid evolution of resistance through selection for partially resistant intermediate mutants (Zhang et al 2011;Baym et al 2016). There is a substantial and growing literature devoted to evaluating different multiple-drug delivery options using in vitro evolution (reviewed in Maclean et al 2010 andPalmer andKishony 2013;Kim et al 2014;Fuentes-Hernandez et al 2015) on the rate of resistance evolution.…”

Section: Impact Summarymentioning

confidence: 99%

“…Drug sanctuaries in time have been shown to select for cost‐free, drug resistant genotypes (Melnyk et al. ) while spatial gradients in drug delivery can lead to fairly rapid evolution of resistance through selection for partially resistant intermediate mutants (Zhang et al. ; Baym et al.…”

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confidence: 99%

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The emergence, maintenance, and demise of diversity in a spatially variable antibiotic regime

Leale

Kassen

2018

Evolution Letters

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Antimicrobial resistance (AMR) is a growing global threat that, in the absence of new antibiotics, requires effective management of existing drugs. Here, we use experimental evolution of the opportunistic human pathogen Pseudomonas aeruginosa to explore how changing patterns of drug delivery modulates the spread of resistance in a population. Resistance evolves readily under both temporal and spatial variation in drug delivery and fixes rapidly under temporal, but not spatial, variation. Resistant and sensitive genotypes coexist in spatially varying conditions due to a resistance‐growth rate trade‐off which, when coupled to dispersal, generates negative frequency‐dependent selection and a quasi‐protected polymorphism. Coexistence is ultimately lost, however, because resistant types with improved growth rates in the absence of drug spread through the population. These results suggest that spatially variable drug prescriptions can delay but not prevent the spread of resistance and provide a striking example of how the emergence and eventual demise of biodiversity is underpinned by evolving fitness trade‐offs.

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Impact Summarymentioning

confidence: 99%

Section: Impact Summarymentioning

confidence: 99%

mentioning

confidence: 99%

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The emergence, maintenance, and demise of diversity in a spatially variable antibiotic regime

Leale

Kassen

2018

Evolution Letters

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The cost of evolved constitutive lac gene expression is usually, but not always, maintained during evolution of generalist populations

Phillips

Cooper

2021

Ecology and Evolution

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Beneficial mutations can become costly following an environmental change. Compensatory mutations can relieve these costs, while not affecting the selected function, so that the benefits are retained if the environment shifts back to be similar to the one in which the beneficial mutation was originally selected. Compensatory mutations have been extensively studied in the context of antibiotic resistance, responses to specific genetic perturbations, and in the determination of interacting gene network components. Few studies have focused on the role of compensatory mutations during more general adaptation, especially as the result of selection in fluctuating environments where adaptations to different environment components may often involve trade‐offs. We examine whether costs of a mutation in lacI, which deregulated the expression of the lac operon in evolving populations of Escherichia coli bacteria, were compensated. This mutation occurred in multiple replicate populations selected in environments that fluctuated between growth on lactose, where the mutation was beneficial, and on glucose, where it was deleterious. We found that compensation for the cost of the lacI mutation was rare, but, when it did occur, it did not negatively affect the selected benefit. Compensation was not more likely to occur in a particular evolution environment. Compensation has the potential to remove pleiotropic costs of adaptation, but its rarity indicates that the circumstances to bring about the phenomenon may be peculiar to each individual or impeded by other selected mutations.

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Identification of Mutations Associated With Macozinone-Resistant in Mycobacterium Tuberculosis

Chen

Wang

et al. 2022

Curr Microbiol

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Macozinone is identified as a drug candidate and is currently under clinical development for the treatment of tuberculosis, but the mutations conferring resistance to Macozinone remain inadequately characterized. Herein, we investigated the Macozinone -resistance -associated mutations through selecting resistant isolates in vitro. Macozinone-resistant isolates were obtained through induction in vitro. The level of Macozinone -resistant strains was confirmed by MABA test. PCR sequencing analysis was carried out on dprE1 gene. Whole Genome Sequencing was performed to identify mutations associated with Macozinone -resistance. The totals of isolates obtained at Macozinone concentrations of 6.4ng/ml, 25.6ng/ml, 50ng/ml and 100ng/ml were 49, 20, 20 and 4 respectively. Among the 49 strains obtained by 6.4ng/ml Macozinone only one strain had C387S mutation in dprE1. C387S is only occurred in high-level resistant isolates (MIC > 500ng/ml). Meanwhile high-level resistance to Macozinone can occur in strains induced at 6.4ng/ml and the frequency of occurrence is low (1/49, 2.04%). The MIC90 of other strains except the strains carrying C387S mutation is at the same level (11.5ng/ml > MIC90 > 2ng/ml). The G61A or G248A mutations in dprE1 was discovered for the first time. Other gene mutations (rv0678, rrs, mbtF, rv2956, et al) were found in low-level resistant strains.Conclusions: High-level resistant isolates can be produced at low concentration of Macozinone. C387S mutation in dprE1 is directly related to high-level resistance.There may be new mechanisms involved in Macozinone-resistance independent of dprE1 mutations.

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Evolution of Cost-Free Resistance under Fluctuating Drug Selection in Pseudomonas aeruginosa

Cited by 54 publications

References 61 publications

The emergence, maintenance, and demise of diversity in a spatially variable antibiotic regime

The emergence, maintenance, and demise of diversity in a spatially variable antibiotic regime

The cost of evolved constitutive lac gene expression is usually, but not always, maintained during evolution of generalist populations

Identification of Mutations Associated With Macozinone-Resistant in Mycobacterium Tuberculosis

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