Abstract B35: The strength of drug selection determines the maximum fitness cost of resistance mutations in culture and xenografts

ABSTRACT It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

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The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2015.2452 ◽

2016 ◽

Vol 283 (1822) ◽

pp. 20152452 ◽

Cited By ~ 10

Author(s):

Qin Qi ◽

Macarena Toll-Riera ◽

Karl Heilbron ◽

Gail M. Preston ◽

R. Craig MacLean

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibiotic Resistance ◽

Low Cost ◽

Fitness Cost ◽

Clinical Settings ◽

Resistance Mutations ◽

Beneficial Mutations ◽

Cost Of Resistance ◽

Compensatory Mutations ◽

The Cost

Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR . Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.

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Idiosyncratic variation in the fitness costs of tetracycline-resistance mutations in Escherichia coli

10.1101/2020.09.12.294355 ◽

2020 ◽

Author(s):

Kyle J. Card ◽

Jalin A. Jordan ◽

Richard E. Lenski

Keyword(s):

Tetracycline Resistance ◽

Fitness Cost ◽

Resistance Mutations ◽

Fitness Costs ◽

Genetic Changes ◽

Phenotypic Resistance ◽

Resistant Lines ◽

Cost Of Resistance ◽

Ecological Success ◽

Resistant Mutants

AbstractA bacterium’s fitness relative to its competitors, both in the presence and absence of antibiotics, plays a key role in its ecological success and clinical impact. In this study, we examine whether tetracycline-resistant mutants are less fit in the absence of the drug than their sensitive parents, and whether the fitness cost of resistance is constant or variable across independently derived lines. Tetracycline-resistant lines suffered, on average, a reduction in fitness of almost 8%. There was substantial among-line variation in the fitness cost. This variation was not associated with the level of phenotypic resistance conferred by the mutations, nor did it vary significantly across several different genetic backgrounds. The two resistant lines with the most extreme fitness costs involved functionally unrelated mutations on different genetic backgrounds. However, there was also significant variation in the fitness costs for mutations affecting the same pathway and even different alleles of the same gene. Our findings demonstrate that the fitness costs of antibiotic resistance do not always correlate with the phenotypic level of resistance or the underlying genetic changes. Instead, these costs reflect the idiosyncratic effects of particular resistance mutations and the genetic backgrounds in which they occur.

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Nonoptimal DNA Topoisomerases Allow Maintenance of Supercoiling Levels and Improve Fitness ofStreptococcus pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00783-10 ◽

2010 ◽

Vol 55 (3) ◽

pp. 1097-1105 ◽

Cited By ~ 8

Author(s):

Luz Balsalobre ◽

María José Ferrándiz ◽

Gabriela de Alba ◽

Adela G. de la Campa

Keyword(s):

Fitness Cost ◽

Fluoroquinolone Resistance ◽

Wild Type ◽

Resistance Mutations ◽

Topoisomerase Iv ◽

Cost Of Resistance ◽

Interspecific Recombination ◽

Dimensional Electrophoresis

ABSTRACTFluoroquinolones, which target gyrase and topoisomerase IV, are used for treatingStreptococcus pneumoniaeinfections. Fluoroquinolone resistance in this bacterium can arise via point mutation or interspecific recombination with genetically related streptococci. Our previous study on the fitness cost of resistance mutations and recombinant topoisomerases identified GyrAE85K as a high-cost change. However, this cost was compensated for by the presence of a recombinant topoisomerase IV (parCandparErecombinant genes) in strain T14. In this study, we purified wild-type and mutant topoisomerases and compared their enzymatic activities. In strain T14, both gyrase carrying GyrAE85K and recombinant topoisomerase IV showed lower activities (from 2.0- to 3.7-fold) than the wild-type enzymes. These variations ofin vitroactivity corresponded to changes ofin vivosupercoiling levels that were analyzed by two-dimensional electrophoresis of an internal plasmid. Strains carrying GyrAE85K and nonrecombinant topoisomerases had lower (11.1% to 14.3%) supercoiling density (σ) values than the wild type. Those carrying GyrAE85K and recombinant topoisomerases showed either partial or total supercoiling level restoration, with σ values being 7.9% (recombinant ParC) and 1.6% (recombinant ParC and recombinant ParE) lower than those for the wild type. These data suggested that changes acquired by interspecific recombination might be selected because they reduce the fitness cost associated with fluoroquinolone resistance mutations. An increase in the incidence of fluoroquinolone resistance, even in the absence of further antibiotic exposure, is envisaged.

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Fitness of Herbicide-Resistant Weeds: Current Knowledge and Implications for Management

Plants ◽

10.3390/plants8110469 ◽

2019 ◽

Vol 8 (11) ◽

pp. 469 ◽

Cited By ~ 5

Author(s):

Vila-Aiub

Keyword(s):

Life History ◽

Herbicide Resistance ◽

Management Practices ◽

Current Knowledge ◽

Resistance Management ◽

Fitness Cost ◽

Plant Fitness ◽

Resistance Mutations ◽

Fitness Costs ◽

Wide Range

Herbicide resistance is the ultimate evidence of the extraordinary capacity of weeds to evolve under stressful conditions. Despite the extraordinary plant fitness advantage endowed by herbicide resistance mutations in agroecosystems under herbicide selection, resistance mutations are predicted to exhibit an adaptation cost (i.e., fitness cost), relative to the susceptible wild-type, in herbicide untreated conditions. Fitness costs associated with herbicide resistance mutations are not universal and their expression depends on the particular mutation, genetic background, dominance of the fitness cost, and environmental conditions. The detrimental effects of herbicide resistance mutations on plant fitness may arise as a direct impact on fitness-related traits and/or coevolution with changes in other life history traits that ultimately may lead to fitness costs under particular ecological conditions. This brings the idea that a “lower adaptive value” of herbicide resistance mutations represents an opportunity for the design of resistance management practices that could minimize the evolution of herbicide resistance. It is evident that the challenge for weed management practices aiming to control, minimize, or even reverse the frequency of resistance mutations in the agricultural landscape is to “create” those agroecological conditions that could expose, exploit, and exacerbate those life history and/or fitness traits affecting the evolution of herbicide resistance mutations. Ideally, resistance management should implement a wide range of cultural practices leading to environmentally mediated fitness costs associated with herbicide resistance mutations.

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Reversing resistance: different routes and common themes across pathogens

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2017.1619 ◽

2017 ◽

Vol 284 (1863) ◽

pp. 20171619 ◽

Cited By ~ 12

Author(s):

Richard C. Allen ◽

Jan Engelstädter ◽

Sebastian Bonhoeffer ◽

Bruce A. McDonald ◽

Alex R. Hall

Keyword(s):

Fitness Cost ◽

Biological Processes ◽

Short Supply ◽

Compensatory Evolution ◽

Wide Range ◽

Different Types ◽

Cost Of Resistance

Resistance spreads rapidly in pathogen or pest populations exposed to biocides, such as fungicides and antibiotics, and in many cases new biocides are in short supply. How can resistance be reversed in order to prolong the effectiveness of available treatments? Some key parameters affecting reversion of resistance are well known, such as the fitness cost of resistance. However, the population biological processes that actually cause resistance to persist or decline remain poorly characterized, and consequently our ability to manage reversion of resistance is limited. Where do susceptible genotypes that replace resistant lineages come from? What is the epidemiological scale of reversion? What information do we need to predict the mechanisms or likelihood of reversion? Here, we define some of the population biological processes that can drive reversion, using examples from a wide range of taxa and biocides. These processes differ primarily in the origin of revertant genotypes, but also in their sensitivity to factors such as coselection and compensatory evolution that can alter the rate of reversion, and the likelihood that resistance will re-emerge upon re-exposure to biocides. We therefore argue that discriminating among different types of reversion allows for better prediction of where resistance is most likely to persist.

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Increased Survival of Antibiotic-Resistant Escherichia coli inside Macrophages

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01632-12 ◽

2012 ◽

Vol 57 (1) ◽

pp. 189-195 ◽

Cited By ~ 33

Author(s):

Migla Miskinyte ◽

Isabel Gordo

Keyword(s):

Escherichia Coli ◽

Antibiotic Resistance ◽

Bacterial Infections ◽

Resistance Mutation ◽

Fitness Cost ◽

Resistance Mutations ◽

Content Type ◽

E Coli ◽

Fitness Effects ◽

K 12

ABSTRACTMutations causing antibiotic resistance usually incur a fitness cost in the absence of antibiotics. The magnitude of such costs is known to vary with the environment. Little is known about the fitness effects of antibiotic resistance mutations when bacteria confront the host's immune system. Here, we study the fitness effects of mutations in therpoB,rpsL, andgyrAgenes, which confer resistance to rifampin, streptomycin, and nalidixic acid, respectively. These antibiotics are frequently used in the treatment of bacterial infections. We measured two important fitness traits—growth rate and survival ability—of 12Escherichia coliK-12 strains, each carrying a single resistance mutation, in the presence of macrophages. Strikingly, we found that 67% of the mutants survived better than the susceptible bacteria in the intracellular niche of the phagocytic cells. In particular, allE. colistreptomycin-resistant mutants exhibited an intracellular advantage. On the other hand, 42% of the mutants incurred a high fitness cost when the bacteria were allowed to divide outside of macrophages. This study shows that single nonsynonymous changes affecting fundamental processes in the cell can contribute to prolonged survival ofE. coliin the context of an infection.

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