Evolutionary Trajectories to Antibiotic Resistance

Abstract

The ability to predict the evolutionary trajectories of antibiotic resistance would be of great value in tailoring dosing regimens of antibiotics so as to maximize the duration of their usefulness. Useful prediction of resistance evolution requires information about (a) the mutation supply rate, (b) the level of resistance conferred by the resistance mechanism, (c) the fitness of the antibiotic-resistant mutant bacteria as a function of drug concentration, and (d) the strength of selective pressures. In addition, processes including epistatic interactions and compensatory evolution, coselection of drug resistances, and population bottlenecks and clonal interference can strongly influence resistance evolution and thereby complicate attempts at prediction. Currently, the very limited quantitative data on most of these parameters severely limit attempts to accurately predict trajectories of resistance evolution.

Effect of environment on the evolutionary trajectories and growth characteristics of antibiotic-resistant Escherichia coli mutants

“…The prospect of using reproducible evolutionary trajectories to resistance as a tool to control the emergence and persistence of AMR is a growing area of research [2,3]. One of the prerequisites for translation of these ideas to the clinic in the form of prescription policy advice is robust and reproducible data which can convince clinicians and policy makers that what is seen in the laboratory is likely to occur in patients.…”

“…In recent years, and in direct response to the global rise in antimicrobial resistant (AMR) pathogenic bacteria, there has been an increased interest in how resistance develops and becomes fixed within a bacterial population. This ranges from the effect of antimicrobials entering the environment following use in humans and animals [1] to understanding the evolution of antimicrobial resistance and the selective pressure from antimicrobials [2,3], with a view to developing new strategies to prevent development of AMR in the future.…”

“…From an evolutionary perspective, there is a particular focus on the effect of acquisition of antimicrobial resistance has on the fitness of bacteria with a view to suppress the development of resistance [3][4][5]. Much of this work relies on the development of resistance in the presence of subinhibitory concentrations of single, or combinations of, antimicrobials and investigators employ a range of different media for the generation of resistance [4,[6][7][8], and the subsequent assessment of fitness related to acquired antimicrobial resistance [9,10].…”

Antimicrobials

“…Bacteria can become resistant in two main ways: the first is that they undergo a genetic mutation that changes an antimicrobial target in some way (Hughes and Andersson 2017) and the second is that they acquire resistance genes from another bacterium or the environment. While the first of these are chance events, the sheer number of bacteria means that such mutations probably occur quite frequently.…”

Antibiotic Resistance Increases Evolvability and Maximizes Opportunities Across Fitness Landscapes

“…It has been proposed that this is due to compensatory mutations (Maisnier-Patin and Andersson 2004). Compensatory mutations relieve the cost of resistance through partial restoration of the impacted phenotype (Reynolds 2000; Szamecz et al 2014; Hughes and Andersson 2017) and have been consistently found in laboratory experiments (Schrag et al 1997; Reynolds 2000; Maisnier-Patin and Andersson 2004). But, compensatory mutations are often absent from clinical strains of antibiotic resistant bacteria (Andersson and Levin 1999; MacLean and Vogwill 2015), suggesting that something more is at play.…”