Deciphering polymicrobial interactions that drive antimicrobial resistance: Molecules, mechanisms and microbiological targets

破译导致抗菌素耐药性的多微生物相互作用：分子、机制和微生物目标

• 批准号: RGPIN-2020-06071
• 负责人: Harrison, Joe
• 金额: $ 3.64万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744756
• 关键词: Deciphering; polymicrobial; interactions; drive; antimicrobial

Background. Antimicrobials are used in nearly every sector of society. In Canada, they are used in animals, are present in hundreds of consumer products, and are commonly dispensed in pharmacies and hospitals. This broad use is associated with the development and spread of resistant microbial populations, making antimicrobial resistance (AMR: the ability of a microorganism to withstand any substance that should kill it or inhibit its growth) one of the greatest public threats of the 21st century. Overarching focus. Microbiologists have acquired most knowledge about the genetic and biochemical mechanisms of AMR by studying model organisms in monocultures. However, bacteria are rarely found in solo groups in any environment; and we know very little about the scope and impact of polymicrobial interactions on the AMR of even the best-studied model microorganisms. This program will address this knowledge gap by elucidating microbial chemical (small molecule) interactions that drive the AMR of bacterial communities. It is predicated on an ecological principle that many Archaea, bacteria and other microbial eukaryotes produce metabolites that modulate AMR due to competition for resources and space in the environment. Progress. My team has led the development of technology platforms for prospecting chemical microbe-microbe interactions. These platforms are now part of Integrated Microbiome Platforms for Advancing Causation Testing and Translation (IMPACTT, the Canadian Microbiome Core). Our platforms include the Alberta Microbiota Repository (a living library of hundreds of species of bacteria and fungi native to Canada) and robotics enclosed in airtight chambers to handle these organisms. We observed that microorganisms producing spent media that can modulate AMR are surprisingly prevalent. Working with experts in natural product chemistry to identify bioactive molecules from complex mixtures, we also identified that many bacteria produce low molecular weight molecules (called N-acylamides) that block AMR, including carbapenem-resistance of Pseudomonas aeruginosa and Acenitobacter baumanii. These carbapenem-resistant bacteria top the World Health Organization (WHO) global priority list of antibiotic-resistant pathogens to guide research, discovery, and development of new antibiotics. Our 5-year aims are to: 1.Identify microbe-microbe interactions and bioactive small metabolites that modulate AMR. 2.Elucidate the mode-of-action through which N-acylamides exert antimicrobial potentiation using chemical and molecular genetic approaches. 3.Investigate the genetics and biochemistry of N-acylamide biosynthesis in bacteria. 4.Develop models to measure the AMR and fitness of organisms in polymicrobial communities. IMPACT. Results will enable researchers and policy makers to devise truly novel strategies for controlling and treating antimicrobial resistant pathogens that cause plant, animal and human infections.

背景抗菌药物几乎应用于社会的各个领域。在加拿大，它们用于动物，存在于数百种消费品中，通常在药店和医院中分发。这种广泛使用与耐药微生物种群的发展和传播有关，使抗菌素耐药性（AMR：微生物抵抗任何应杀死它或抑制其生长的物质的能力）成为21世纪世纪最大的公共威胁之一。过度专注。微生物学家通过研究单一培养物中的模式生物获得了关于AMR的遗传和生化机制的大部分知识。然而，在任何环境中，细菌很少单独存在;我们对多微生物相互作用的范围和影响知之甚少，即使是研究最好的模型微生物也是如此。该计划将通过阐明驱动细菌群落AMR的微生物化学（小分子）相互作用来解决这一知识缺口。基于生态学原理，许多细菌、细菌和其他微生物真核生物由于竞争环境中的资源和空间而产生调节AMR的代谢物。中求进工作总我的团队领导了探索化学微生物-微生物相互作用的技术平台的开发。这些平台现在是推进因果关系测试和翻译的综合微生物组平台（IMPACTT，加拿大微生物组核心）的一部分。我们的平台包括阿尔伯塔微生物库（加拿大本土数百种细菌和真菌的活库）和封闭在密闭室中处理这些生物体的机器人。我们观察到产生可以调节AMR的废培养基的微生物令人惊讶地普遍。与天然产物化学专家合作，从复杂的混合物中鉴定生物活性分子，我们还鉴定出许多细菌产生低分子量分子（称为N-酰胺），这些分子可阻断AMR，包括铜绿假单胞菌和鲍曼不动杆菌的碳青霉烯类耐药性。这些碳青霉烯类耐药细菌在世界卫生组织（WHO）的耐药病原体全球优先列表中名列前茅，以指导新抗生素的研究，发现和开发。我们的5年目标是：1.确定微生物-微生物相互作用和调节AMR的生物活性小代谢物。2.通过化学和分子遗传学方法阐明N-酰胺发挥抗菌增效作用的作用模式。3.研究细菌中N-酰胺生物合成的遗传学和生物化学。4.开发模型来测量AMR和多微生物群落中生物体的适合度。冲击研究结果将使研究人员和政策制定者能够制定真正新颖的战略，以控制和治疗导致植物，动物和人类感染的耐药性病原体。