Evolutionary dynamics of combinational antimicrobial treatments

联合抗菌治疗的演变动力学 摘要 由于过度处方和滥用，抗生素正在失去其效力，由于出现 以及抗药性细菌的迅速增加。不同类型的抗生素，β-内酰胺类 自从青霉素被发现以来，它已被用于治疗大多数感染。 从那时起，细菌对β-内酰胺类抗生素的耐药性，介导的生产延长 超广谱β-内酰胺酶（ESBL）已变得普遍。使用β-内酰胺酶 (Bla)抑制剂可以恢复β-内酰胺类药物对耐药细菌的疗效， 这是必要的，以保护现有的抗生素，面对投资下降， 新的抗生素然而，联合治疗对β-内酰胺选择的影响 抵抗力还没有被很好地理解。由于Bla的产生有益于抗性细胞， 生长敏感细胞，这些益处可能受到以下因素的不同影响： Bla抑制剂的引入，导致非直观的进化动力学。我们 初步研究表明，联合治疗的进化影响取决于 三种菌株特异性因素：生产细胞对 抗生素在单个细胞水平，在何种程度上抑制剂可以抑制这种 抗性和Bla生产的负担。特别是，对于Bla变体， 更大程度的私人利益（对于生产细胞），联合治疗可以 基本上选择抗性部分。然而，对于主要用作 作为一种公共产品，联合治疗将非常有效地选择 抗性细胞我们提议的研究将深入研究这些进化动力学 使用数学建模和定量实验的组合。特别是， 我们将使用工程细菌作为良好控制的模型系统来测试预测的 进化动力学然后，我们将通过使用 由耐药病原体和敏感细菌组成的微生物群落。 从拟议的工作中获得的见解对指导有效设计 针对β-内酰胺抗性细菌病原体的组合治疗。

Evolutionary dynamics of combinational antimicrobial treatments Abstract Due to over-prescription and misuse, antibiotics are losing their efficacy due to emergence and rapid rise of antibiotic-resistant bacteria. Of different types of antibiotics, β-lactams have been prescribed to treat the majority of infections since the discovery of penicillin. Since then, bacterial resistance to β-lactams, mediated by the production of extended spectrum β-lactamase (ESBL) enzymes, has become widespread. Using β-lactamase (Bla) inhibitors can restore the efficacy of β-lactams against resistant bacteria, a strategy which is necessary to preserve existing antibiotics in the face of declining investment in new antibiotics. However, the effect of combination treatment on selection for β-lactam resistance is not well understood. Since Bla production benefits both resistant cells and growth-advantaged sensitive cells, and these benefits may be differentially impacted by the introduction of Bla inhibitor, leading to non-intuitive evolutionary dynamics. Our preliminary work suggests that the evolutionary impact of combination treatment depends on three strain-specific factors: the extent to which producing cells are resistant to the antibiotic at the individual cell level, the extent to which the inhibitor can suppress this resistance, and the burden of Bla production. In particular, for Bla variants that offer a greater degree of private benefit (for the producing cells), the combination treatment can substantially select for the resistant fraction. However, for variants that primarily serve as a public good, the combination treatment will be highly effective in selecting against the resistant cells. Our proposed research will examine these evolutionary dynamics in depth using a combination of mathematical modeling and quantitative experiments. In particular, we will use engineered bacteria as well-controlled model systems to test the predicted evolutionary dynamics. Then, we will test the predicted evolutionary dynamics by using microbial communities consisting of both resistant pathogens and sensitive bacteria. Insights learned from the proposed work have implications for guiding effective design of combination treatments against β-lactam-resistant bacterial pathogens.