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

背景。抗微生物药物几乎用于社会的每个部门。在加拿大，它们用于动物，存在于数百种消费品中，并且通常在药房和医院配发。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其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。包罗万象的焦点。微生物学家通过对单培养模式生物的研究，获得了有关抗菌素耐药性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对AMR的范围和影响知之甚少，即使是研究得最好的模式微生物。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差距。根据生态学原理，许多古细菌、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。的进步。我的团队领导了寻找化学微生物-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转化的综合微生物组平台（IMPACTT，加拿大微生物组核心）的一部分。我们的平台包括艾伯塔省微生物库（加拿大本土数百种细菌和真菌的活库）和封闭在密闭室中的机器人来处理这些生物。我们观察到，产生可以调节抗菌素耐药性的废培养基的微生物出奇地普遍。我们与天然产物化学方面的专家合作，从复杂的混合物中鉴定出生物活性分子。我们还发现，许多细菌产生的低分子量分子（称为n -酰基酰胺）可以阻断抗菌素耐药性，包括铜绿假单胞菌和鲍曼酸杆菌的碳青霉烯耐药性。这些碳青霉烯耐药细菌在世界卫生组织（WHO）全球抗生素耐药病原体优先清单中名列前茅，以指导新抗生素的研究、发现和开发。我们的5年目标是：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模式。3.研究细菌n -丙烯酰胺生物合成的遗传学和生物化学。4.开发模型来测量多微生物群落中生物的抗菌素耐药性和适合度。的影响。研究结果将使研究人员和决策者能够设计出真正新颖的策略来控制和治疗引起植物、动物和人类感染的抗微生物药物耐药性病原体。

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.