Department of Physics, University of Alberta, 11455 Saskatchewan Drive NW, Edmonton, Alberta, Canada.
Department of Biological Sciences, University of Alberta, 11455 Saskatchewan Drive NW, Edmonton, Alberta, Canada.
Phys Biol. 2022 Sep 8;19(6). doi: 10.1088/1478-3975/ac8c17.
Rising rates of resistance to antimicrobial drugs threaten the effective treatment of infections across the globe. Drug resistance has been established to emerge from non-genetic mechanisms as well as from genetic mechanisms. However, it is still unclear how non-genetic resistance affects the evolution of genetic drug resistance. We develop deterministic and stochastic population models that incorporate resource competition to quantitatively investigate the transition from non-genetic to genetic resistance during the exposure to static and cidal drugs. We find that non-genetic resistance facilitates the survival of cell populations during drug treatment while hindering the development of genetic resistance due to competition between the non-genetically and genetically resistant subpopulations. Non-genetic resistance in the presence of subpopulation competition increases the fixation times of drug resistance mutations, while increasing the probability of mutation before population extinction during cidal drug treatment. Intense intraspecific competition during drug treatment leads to extinction of susceptible and non-genetically resistant subpopulations. Alternating between drug and no drug conditions results in oscillatory population dynamics, increased resistance mutation fixation timescales, and reduced population survival. These findings advance our fundamental understanding of the evolution of resistance and may guide novel treatment strategies for patients with drug-resistant infections.
耐药率的上升威胁着全球感染的有效治疗。耐药性已经确立，可以从非遗传机制以及遗传机制中产生。然而，非遗传耐药性如何影响遗传耐药性的进化仍然不清楚。我们开发了确定性和随机性的群体模型，纳入资源竞争，以定量研究在接触静态和杀菌药物时，非遗传耐药性向遗传耐药性的转变。我们发现，非遗传耐药性在药物治疗期间促进了细胞群体的存活，同时由于非遗传和遗传耐药亚群之间的竞争，阻碍了遗传耐药性的发展。在亚群竞争存在的情况下，非遗传耐药性增加了耐药性突变的固定时间，同时增加了在杀菌药物治疗期间种群灭绝前发生突变的概率。药物治疗期间强烈的种内竞争导致易感和非遗传耐药亚群的灭绝。在药物和无药物条件之间交替会导致种群动态的振荡、耐药性突变固定时间尺度的增加和种群生存能力的降低。这些发现推进了我们对耐药性进化的基本理解，并可能为耐药感染患者提供新的治疗策略。
