Multi-step vs. single-step resistance evolution under different drugs, pharmacokinetics, and treatment regimens

Abstract

The success of antimicrobial treatment is threatened by the evolution of drug resistance. Population genetic models are an important tool in mitigating that threat. However, most such models consider resistance emergence via a single mutational step. Here, we assembled experimental evidence that drug resistance evolution follows two patterns: i) a single mutation, which provides a large resistance benefit, or ii) multiple mutations, each conferring a small benefit, which combine to yield high-level resistance. Using stochastic modeling we then investigated the consequences of these two patterns for treatment failure and population diversity under various treatments. We find that resistance evolution is substantially limited if more than two mutations are required and that the extent of this limitation depends on the combination of drug type and pharmacokinetic profile. Further, if multiple mutations are necessary, adaptive treatment, which only suppresses the bacterial population, delays treatment failure due to resistance for a longer time than aggressive treatment, which aims at eradication.

Colistin-phage combinations decrease antibiotic resistance in Acinetobacter baumannii via changes in envelope architecture

“…Molecular mechanisms of resistance have evolved for most antibiotics, which are then quickly distributed throughout bacterial populations by horizontal gene transfer. This is primarily mediated by plasmids and integrative and conjugative elements [ 2–4 ]. At the same time, the slow and expensive discovery process and clinical development of antimicrobial compounds together with the lack of monetary incentives have resulted in continuously decreasing numbers of effective drugs to treat bacterial infections [ 5 , 6 ].…”

Modeling Polygenic Antibiotic Resistance Evolution in Biofilms

“…This means that the replication rate of the resistant mutant is often slower in the drug-free environment, and the resistant mutations are either present at low frequencies or completely purged from the population. Note, however, that the trade-off for resistance mutation acquisition is still an open question (Melnyk and Kassen, 2011 ; Igler et al, 2021 ), and compensatory mutations might mitigate the fitness loss.…”

“…It is now widely accepted that multiple genes of various effects determine antibiotic resistance in planktonic bacteria (Petchiappan and Chatterji, 2017 ; Apjok et al, 2019 ; Igler et al, 2021 ). Similarly, multiple mutations were recently implicated in biofilm recalcitrance (Santos-Lopez et al, 2019 ; Santos-Lopez and Cooper, 2021 ).…”

Evolutionary medicine

“…Basic and applied questions in this area of evolutionary medicine research include: How does resistance develop and spread? How repeatable is it (Igler et al, 2021)? What cultural factors -beyond the drug treatment itselfplay major roles in this process?…”