Microbial exploration for new antimicrobial discovery

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications, trials & patents

Abstract

The human microbiome contributes to the overall health of its host through multiple mechanisms, including nutrient breakdown and colonization resistance to pathogens. As a result, microbial imbalance in the human microbiome has been linked to a wide range of diseases. Our research focuses on the intersection of microbiome function and human health with the overarching goal of developing microbiome-based therapeutics to treat diseases. There are two key questions that we aim to address; (i) can we uncover microbial associations with diseases using new tools that will otherwise not be detected using traditional methods? (ii) Can we modulate the microbiome as a clinical intervention by specifically targeting a microbe of interest without disrupting the microbiome? To answer the first question (Aim 1), we have developed new approaches for functional characterization of the microbiome. In particular, we developed an approach that can detect pseudouridines in bacterial mRNAs at single base resolution. We show that this approach can identify microbial genes associated with different environmental conditions which are typically difficult to detect using conventional approaches. In Aim 2, our goal is to develop taxa-specific antimicrobials to modulate the microbiome using an antimicrobial prodrug or phage therapy approach. For our studies, our initial focus is on Porphyromonas gingivalis, a keystone pathogen involved in periodontitis. We have developed an antimicrobial prodrug (MTU02) that selectively targets P. gingivalis. In in vitro tests, this prodrug was readily activated in the presence of multiple strains of P. gingivalis while remaining inactive against other bacterial species. Additionally, a single, low dose concentration of MTU02 specifically inhibited the growth of P. gingivalis in subgingival microbiome samples derived from periodontitis patients. Importantly, there was no significant disruption in the abundance and composition of oral commensals. In further in vivo tests using a ligature-induced periodontitis mice model, MTU02 suppressed the growth of P. gingivalis and significantly decreased alveolar bone loss with minimal disruption to the microbiome composition. Altogether, we expect that findings from our work will provide new toolsets to study the microbiome at the functional level and provide therapies for precise manipulation of the microbiome.