Bottleneck size and selection level reproducibly impact evolution of antibiotic resistance

Abstract

During antibiotic treatment, the evolution of bacterial pathogens is fundamentally affected by bottlenecks and varying selection levels imposed by the drugs. Bottlenecks—that is, reductions in bacterial population size—lead to an increased influence of random effects (genetic drift) during bacterial evolution, and varying antibiotic concentrations during treatment may favour distinct resistance variants. Both aspects influence the process of bacterial evolution during antibiotic therapy and thereby treatment outcome. Surprisingly, the joint influence of these interconnected factors on the evolution of antibiotic resistance remains largely unexplored. Here we combine evolution experiments with genomic and genetic analyses to demonstrate that bottleneck size and antibiotic-induced selection reproducibly impact the evolutionary path to resistance in pathogenic Pseudomonas aeruginosa, one of the most problematic opportunistic human pathogens. Resistance is favoured—expectedly—under high antibiotic selection and weak bottlenecks, but—unexpectedly—also under low antibiotic selection and severe bottlenecks. The latter is likely to result from a reduced probability of losing favourable variants through drift under weak selection. Moreover, the absence of high resistance under low selection and weak bottlenecks is caused by the spread of low-resistance variants with high competitive fitness under these conditions. We conclude that bottlenecks, in combination with drug-induced selection, are currently neglected key determinants of pathogen evolution and outcome of antibiotic treatment.

Modelling within-host evolutionary dynamics of antimicrobial resistance

“…The advantage of the proposed modelling approach is that it allows for AMR to be represented as a continuous quantitative trait, describing the level of resistance of the bacterial population termed quantitative AMR (qAMR) in [3]. Moreover, consistent with recent experimental evidence [2] integro-differential equations take into account both, the dynamics of the bacterial population density, referred to as "bottleneck size" in [2] as well as the evolution of its level of resistance due to drug-induced selection.…”

“…The latter has been referred to as within-host evolution of antimicrobial resistance and studied in infectious disease settings such as Tuberculosis [1]. During antibiotic treatment for example within-host evolutionary AMR dynamics plays an important role [2] and presents significant challenges in terms of optimizing treatment dosage. The study by Djidjou-Demasse et al [3] contributes to addressing such challenges by developing a modelling approach that utilizes integro-differential equations to mathematically capture continuity in the space of the bacterial resistance levels.…”

Extensively Drug-Resistant Klebsiella pneumoniae Counteracts Fitness and Virulence Costs That Accompanied Ceftazidime-Avibactam Resistance Acquisition

“…One limitation of our study is the “random” nature of mutations and transcriptomic and phenotypic changes, which might present differently upon repetition of the experiment. Moreover, during (experimental) evolution, numerous factors, such as variations in population size and selection pressure ( 113 ), might directly influence adaptational events. However, this does not diminish the significance of our findings but underlines the diversity of resistance evolution, compensation, and underlying processes.…”

A selective bottleneck during host entry drives the evolution of new legume symbionts

“…These results shed light on the importance of selective bottlenecks in shaping the evolutionary trajectories of emerging microbial symbionts. Most theoretical 31,32 and experimental [33][34][35][36][37][38] works on the influence of bottlenecks on microbial adaptation have focused on non-selective bottlenecks that randomly purge genetic diversity and reduce the efficiency of natural selection. Yet, another aspect of bottlenecks emerges when considering that transmission and host colonization can be, at least partially, dependent on microbial genotype, prompting us to consider infection bottlenecks as selective events 39 .…”