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

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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.