Evolutionary dynamics of combinational antimicrobial treatments

组合抗菌治疗的进化动力学

• 批准号: 10445962
• 负责人: LINGCHONG YOU
• 金额: $ 30.36万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445962
• 关键词: Active Sites; Adjuvant; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Binding; Biological Assay; Biological Models; Cells; Cessation of life; Clinical; Clinical Treatment; Computer Models; Economics; Engineering; Enterobacteriaceae; Enzymes; Extended-spectrum β-lactamase; Formulation; Gram-Negative Bacteria; Growth; Health Care Costs; Hydrolysis; Incidence; Individual; Infection; Inpatients; Investments; Life; Measures; Mediating; Metabolic; Modeling; Outcome; Outpatients; Penetration; Penicillins; Physiological; Population; Population Heterogeneity; Privatization; Production; Public Health; Regimen; Research; Resistance; Resistance development; System; Testing; Thinness; Treatment Efficacy; United States; Variant; Work; antimicrobial; bacterial resistance; base; beta-Lactam Resistance; beta-Lactamase; beta-Lactams; cell growth; design; effective therapy; efficacy testing; experimental study; inhibitor; insight; mathematical model; microbial community; misuse of prescription only drugs; mortality; novel; pathogen; pathogenic bacteria; periplasm; predictive modeling; predictive test; preservation; prevent; resistance mechanism; response; treatment strategy

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.

组合抗菌治疗的进化动力学 抽象的 由于过度处方和滥用，抗生素因出现而失去功效 以及抗生素耐药细菌的迅速增加。不同类型的抗生素中，β-内酰胺类 自发现青霉素以来，已被用于治疗大多数感染。 从那时起，细菌对β-内酰胺的耐药性通过产生延长的介导而介导。 光谱β-内酰胺酶（ESBL）酶已变得广泛使用。使用β-内酰胺酶 (Bla)抑制剂可以恢复β-内酰胺对抗耐药菌的功效，这是一种策略 面对投资下降，这是保护现有抗生素所必需的 新抗生素。然而，联合治疗对β-内酰胺选择的影响 阻力还没有被很好地理解。由于 Bla 生产对耐药细胞和 生长有利的敏感细胞，这些益处可能会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。我们的 初步工作表明，联合治疗的进化影响取决于 三个菌株特异性因素：生产细胞对菌株的抵抗程度 单个细胞水平上的抗生素，抑制剂可以抑制这种情况的程度 阻力和 Bla 生产的负担。特别是，对于提供以下功能的 Bla 变体 更大程度的私人利益（对于生产细胞），联合治疗可以 基本上选择抗性分数。然而，对于主要用作 作为一项公共利益，联合治疗将非常有效地选择 耐药细胞。我们提出的研究将深入研究这些进化动力学 结合数学建模和定量实验。尤其， 我们将使用工程细菌作为控制良好的模型系统来测试预测的结果 进化动力学。然后，我们将使用以下方法测试预测的进化动力学 由耐药病原体和敏感细菌组成的微生物群落。 从拟议工作中获得的见解对于指导有效的设计具有重要意义 针对β-内酰胺耐药细菌病原体的联合治疗。