Sorbonne Université, CNRS, Institut de Biologie Paris-Seine, Laboratoire Jean Perrin (UMR 8237), F-75005 Paris, France.
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
PLoS Comput Biol. 2020 Apr 10;16(4):e1007798. doi: 10.1371/journal.pcbi.1007798. eCollection 2020 Apr.
The evolution of antimicrobial resistance can be strongly affected by variations of antimicrobial concentration. Here, we study the impact of periodic alternations of absence and presence of antimicrobial on resistance evolution in a microbial population, using a stochastic model that includes variations of both population composition and size, and fully incorporates stochastic population extinctions. We show that fast alternations of presence and absence of antimicrobial are inefficient to eradicate the microbial population and strongly favor the establishment of resistance, unless the antimicrobial increases enough the death rate. We further demonstrate that if the period of alternations is longer than a threshold value, the microbial population goes extinct upon the first addition of antimicrobial, if it is not rescued by resistance. We express the probability that the population is eradicated upon the first addition of antimicrobial, assuming rare mutations. Rescue by resistance can happen either if resistant mutants preexist, or if they appear after antimicrobial is added to the environment. Importantly, the latter case is fully prevented by perfect biostatic antimicrobials that completely stop division of sensitive microorganisms. By contrast, we show that the parameter regime where treatment is efficient is larger for biocidal drugs than for biostatic drugs. This sheds light on the respective merits of different antimicrobial modes of action.
抗生素耐药性的进化会受到抗生素浓度变化的强烈影响。在这里，我们使用一个随机模型来研究在微生物种群中，抗生素的周期性缺失和存在交替对耐药性进化的影响，该模型包括种群组成和大小的变化，并充分纳入了随机种群灭绝。我们表明，快速的抗生素缺失和存在交替对消灭微生物种群效率不高，并且强烈促进了耐药性的建立，除非抗生素足够增加死亡率。我们进一步证明，如果交替周期长于一个阈值，则如果没有耐药性来拯救，微生物种群将在第一次添加抗生素时灭绝。我们在稀有突变的假设下表示，在第一次添加抗生素时，种群被消灭的概率。耐药性的拯救要么是因为存在耐药突变体，要么是因为它们在抗生素添加到环境后出现。重要的是，完全阻止敏感微生物分裂的完美抑菌抗生素完全防止了后一种情况的发生。相比之下，我们表明，对于杀菌药物来说，治疗有效的参数范围大于抑菌药物。这揭示了不同抗生素作用模式的各自优点。
