Identification of antimicrobial specialized metabolites from the human oral microbiome to target multidrug-resistant pathogens

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PROJECT SUMMARY / ABSTRACT Our microbiome plays a key role in colonization resistance, which is the prevention of growth, persistence, and subsequent infection by pathogenic microorganisms. Disruptions in an established microbial community and its functioning can alter infection susceptibility. Understanding how changes in the oral microbiome render it vulnerable to pathogen colonization is essential, as carriage of drug-resistant microbes is a major risk factor for developing serious and difficult-to-treat infections. One mechanism by which our microbiome acts to prevent pathogen colonization is through the production of antimicrobial specialized metabolites (ASMs) that directly inhibit the growth of competing microbes. Identification of such bioactive metabolites can be facilitated by examining the biosynthetic gene clusters (BGC) that encode them. Analysis of reference genomes generated through the Human Microbiome Project identified 3,118 BGCs across various body sites, with the typical oral cavity containing high BGC abundance (1,061+/-143 clusters). The microbiota inhabiting this site represent a first point of contact with the environment and invading microbes, and therefore, play a vital gatekeeping role against pathogen dissemination to the lower gastrointestinal and respiratory tracts. Yet, the structure and function of ASMs produced by human-associated microbiota remains limited, particularly within the oral cavity. This proposal seeks to leverage a combination of comparative metagenomic and metabolomic approaches to determine the role of ASM production by oral-associated bacteria in defense against multidrug-resistant organisms (MDRO). The specific aims are to 1) define differences in oral microbiomes between MDRO carriers versus non-carriers and assess how determinants of health associate with abundance of key taxa, and 2) evaluate the production of bioactive ASMs by oral-associated bacteria from MDRO carriers versus non-carriers. These objectives will be accomplished through shotgun metagenomic sequencing of oral microbiome samples from diverse populations, paired with analysis of detailed associated metadata relating to health and MDRO carriage risk factors. Identification of antimicrobial metabolite producing bacteria will be achieved through high-throughput bioactivity-guided fractionation, followed by metabolomic analysis and in vivo efficacy testing. The study of ASM production by oral microbiota will yield insight into the factors shaping this dynamic microbial community and serve as an untapped source for much-needed, new antimicrobial drug leads. The unmatched caliber of microbiology research performed at the University of Wisconsin-Madison will provide an ideal environment to carry out the proposed work. Resources and mentorship provided by project sponsor Dr. Cameron Currie and collaborators will facilitate the timely completion of this proposal. Moreover, execution of this tailored research training plan will enable the applicant to develop the necessary experimental, communication, and clinical skills for a successful transition to a career as a physician-scientist.