Mapping polymicrobial interactions that modulate antibiotic persistence

摘要： 世纪早期抗生素的发现改变了现代医学;然而几十年的使用， 过度使用和误用导致现有药物难以治愈的病原体迅速增加。 抗生素耐药性不是治疗失败的唯一原因。在对抗生素敏感的文化中， 细菌的亚群可以短暂地重新编程它们的表型，这使它们能够在致命的环境中存活下来。 抗生素剂量这些细菌持续存在被认为是复发性和慢性感染的基础， 可以促进抗药性的发展越来越多的证据表明，环境因素 表型变化导致治疗前、治疗中和治疗后的抗生素持久性。因此，实现A 更深入地了解环境线索，细菌表型反应之间的相互作用， 抗生素敏感性将提高我们设计更有效治疗方案的能力。 当病原体定殖并感染宿主的不同部位时，它们通常暴露于其他病原体， 宿主微生物组的组成部分。微生物相互作用调节病原体的程度 表型和抗生素持久性仍然在很大程度上未被探索。我们这个项目的首要目标是 系统研究微生物组成分对金黄色葡萄球菌表型的影响， 对抗生素的反应和持久性。为了实现这一目标，我们将开发共培养表型筛选 以确定影响S.金黄色葡萄球菌抗生素持久性对不同 抗生素的种类使用转录组学，代谢组学和单细胞方法的组合，我们 将决定这些微生物相互作用如何调节S.金黄色葡萄球菌表型（在人群和单个 细胞水平）在抗生素治疗之前、期间和之后。我们还将使用分析技术来识别 介导微生物相互作用的分子决定因素，对S.金黄色 持久性。我们设想，这个项目的结果将扩大我们的知识persister 表型，有助于发现新的抗微生物佐剂，并指导 创新的治疗策略，以应对慢性感染。

Abstract: The discovery of antibiotics in the early 20th century has transformed modern medicine; yet decades of use, overuse, and misuse have culminated in the rapid rise in pathogens that are refractory to our existing drugs. Antibiotic resistance is not the only reason for treatment failure. Within antibiotic-sensitive cultures, subpopulations of bacteria can transiently reprogram their phenotype, which enable them to survive lethal antibiotic doses. These bacterial persisters are thought to underlie recurrent and chronic infections, and they can fuel the development of resistance. Mounting evidence shows that environmental factors modulate phenotypic changes that lead to antibiotic persistence before, during, and after treatment. As such, achieving a deeper understanding of the interplay between environmental cues, bacterial phenotypic responses, and antibiotic susceptibility will improve our ability to devise more effective treatment regimens. When pathogens colonize and infect different parts of the host, they are often exposed to other pathogens and constituents of the host microbiome. The extent to which microbial interactions modulate a pathogen's phenotype and antibiotic persistence remains largely unexplored. Our overarching objective for this project is to systematically investigate the impact of microbiome constituents on Staphylococcus aureus's phenotypic response and persistence to antibiotics. To achieve this goal, we will develop a co-culturing phenotypic screen to identify bacterial strains and communities that impact S. aureus antibiotic persistence toward distinct classes of antibiotics. Using a combination of transcriptomics, metabolomics, and single-cell approaches, we will determine how these microbial interactions modulate S. aureus phenotypes (on the population- and single- cell level) before, during, and after antibiotic treatment. We will also use analytical techniques to identify molecular determinants that mediate microbial interactions responsible for the strongest effect on S. aureus persistence. We envision that the outcome of this project will expand our knowledge of the persister phenotype, contribute to the discovery of novel antimicrobial adjuvants, and guide the development of innovative treatment strategies to tackle chronic infections.