Mapping polymicrobial interactions that modulate antibiotic persistence

绘制调节抗生素持久性的多种微生物相互作用

• 批准号: 10240967
• 负责人: Wendy W.K. Mok
• 金额: $ 147.6万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240967
• 关键词: Adjuvant; Aftercare; Antibiotic Resistance; Antibiotic Therapy; Antibiotic susceptibility; Antibiotics; Bacteria; Cells; Coculture Techniques; Communities; Cues; Development; Dose; Environmental Risk Factor; Exposure to; Goals; Knowledge; Lead; Mediating; Modern Medicine; Molecular; Outcome; Pharmaceutical Preparations; Phenotype; Population; Public Health; Refractory; Resistance development; Staphylococcus aureus; Techniques; Treatment Failure; Treatment Protocols; Work; antimicrobial; chronic infection; effective therapy; host microbiome; improved; innovation; metabolomics; microbiome; microorganism interaction; novel; pathogen; persistent bacteria; recurrent infection; response; transcriptomics; treatment strategy

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.

抽象的： 在20世纪初期发现抗生素的发现改变了现代医学。数十年来的使用， 过度使用和滥用已导致对我们现有药物难治的病原体的快速增加。 抗生素耐药性并不是治疗失败的唯一原因。在抗生素敏感的培养物中， 细菌的亚群可以瞬时重新编程其表型，从而使其能够生存致命 抗生素剂量。这些细菌的坚持被认为是经常性和慢性感染的基础，它们是 可以推动阻力的发展。安装证据表明，环境因素调节 表型变化导致治疗前，期间和之后导致抗生素持久性。因此，实现 对环境线索，细菌表型反应和 抗生素易感性将提高我们设计更有效治疗方案的能力。 当病原体定居并感染宿主的不同部位时，它们通常会暴露于其他病原体和 宿主微生物组的成分。微生物相互作用调节病原体的程度 表型和抗生素持久性在很大程度上尚未探索。我们这个项目的总体目标是 系统地研究微生物组成分对金黄色葡萄球菌的表型的影响 对抗生素的反应和持久性。为了实现这一目标，我们将开发一个共同培养的表型屏幕 识别影响金黄色葡萄球菌抗生素持久性的细菌菌株和社区 抗生素类。使用转录组学，代谢组学和单细胞方法的组合，我们 将确定这些微生物相互作用如何调节金黄色葡萄球菌表型（在种群和单一的 细胞水平）抗生素治疗前，期间和之后。我们还将使用分析技术来识别 介导对金黄色葡萄球菌最大作用的微生物相互作用的分子决定因素 持久性。我们设想该项目的结果将扩大我们对毅力的了解 表型，有助于发现新型抗菌佐剂，并指导 解决慢性感染的创新治疗策略。