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

背景资料。几乎社会的每一个部门都在使用抗菌剂。在加拿大，它们被用于动物，存在于数百种消费品中，并通常在药店和医院分发。这种广泛的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：微生物抵抗任何应该杀死它或抑制其生长的物质的能力)成为21世纪最大的公共威胁之一。全神贯注。微生物学家通过研究单一培养的模式生物，已经获得了关于AMR的遗传和生化机制的大部分知识。然而，细菌在任何环境中都很少单独存在；我们对多微生物相互作用的范围和对AMR的影响知之甚少，即使是研究最深入的模式微生物也是如此。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鸿沟。它是基于一个生态学原理，即许多古生菌、细菌和其他微生物真核生物由于对环境中资源和空间的竞争而产生调节AMR的代谢物。进步。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集成微生物组平台(Impactt，加拿大微生物组核心)的一部分。我们的平台包括艾伯塔省微生物群储存库(加拿大本土数百种细菌和真菌的活体图书馆)和封闭在密封室中的机器人来处理这些微生物。我们观察到，产生能够调节AMR的废培养基的微生物出人意料地普遍。我们还与天然产物化学专家合作，从复杂的混合物中识别生物活性分子，我们还发现许多细菌产生能阻断AMR的低分子分子(称为N-酰胺)，包括铜绿假单胞菌和鲍曼不动杆菌的碳青霉烯耐药性。这些耐碳青霉烯类细菌位居世界卫生组织(WHO)全球耐药病原体优先名单之首，以指导新抗生素的研究、发现和开发。我们五年的目标是：1.鉴定微生物-微生物相互作用和调节AMR的生物活性小代谢物。2.利用化学和分子遗传学方法阐明N-酰基酰胺发挥抗菌增强作用的作用方式。3.研究细菌中N-酰基酰胺生物合成的遗传学和生物化学。4.开发多种微生物群落中生物的AMR和适合度的测量模型。冲击力。研究结果将使研究人员和政策制定者能够设计出真正新颖的战略，以控制和治疗导致植物、动物和人类感染的抗药性病原体。

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.