Abstract
The evolution of antibiotic resistance is influenced by a variety of factors, including the availability of resistance mutations, and the pleiotropic effects of such mutations. Here, we isolate and characterize chromosomal quinolone resistance mutations in E. coli, in order to gain a systematic understanding of the rate and consequences of resistance to this important class of drugs. We isolated over fifty spontaneous resistance mutants on nalidixic acid, ciprofloxacin, and levofloxacin. This set of mutants includes known resistance mutations in gyrA, gyrB, and marR, as well as two novel gyrB mutations. We find that, for most mutations, resistance tends to be higher to nalidixic acid than relative to the other two drugs. Resistance mutations had deleterious impacts on one or more growth parameters, suggesting that quinolone resistance mutations are generally costly. Our findings suggest that the prevalence of specific gyrA alleles amongst clinical isolates are driven by high levels of resistance, at no more cost than other resistance alleles.
Highlights
The increasing prevalence of antimicrobial resistance (AMR) has become an urgent public health problem worldwide
Resistance to ciprofloxacin, the most commonly purchased antimicrobial by hospitals in Canada between 2008–2014 [1], in Escherichia coli rose to 26.7% in 2015 from 21.6% in 2009 [2]
Minimum inhibitory concentration (MIC) values for the ancestral strain and for antibioticresistant mutants were determined for nalidixic acid, ciprofloxacin and levofloxacin (SigmaAldrich) using a 96 well plate assay
Summary
The increasing prevalence of antimicrobial resistance (AMR) has become an urgent public health problem worldwide. Given the rapid increase in the prevalence of resistance, an understanding of the principles underlying resistance evolution is vital. Adaptation, of which the evolution of AMR is a prime example, is driven by the interplay between mutation, selection, and demographic processes like drift. In understanding the evolution of AMR, we are interested in both mutation and selection. For example, that higher mutation rates will generally lead to a more rapid evolution of resistance. The spread of a given mutation will be influenced by its selective consequences, including its effect on resistance, and on its pleiotropic effects, such as fitness in the absence of antibiotic, and collateral sensitivity or cross resistance to other antibiotics
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