Microbial exploration for new antimicrobial discovery

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications, trials & patents

Abstract

The increasing rate of antibiotics resistance bacteria places a huge burden on healthcare systems with significant economic implications. Potential effects include increased cost of treatment and higher mortality/morbidity rates. Despite the obvious need, no approved antibiotic drug class has been discovered since 1980. Of greater worry, no new class of antibiotics has been discovered since 1962 to treat Gram-negative bacteria, which make up the bulk of multi-drug resistant superbugs. On the other hand, microbial dysbiosis from the use of broad-spectrum antimicrobials has also been associated with several diseases, presumably by suppressing the growth of beneficial commensals. The holy grail of microbiome therapeutics is to specifically target an organism of interest while preserving majority of the microbiome. Therefore, while there is a need for the discovery of broad-spectrum antibiotics to treat systemic infections, there is also a need to develop taxa-specific antimicrobials to modulate the microbiome. Our strategy in Aim 1 for the discovery of novel broad-spectrum antimicrobial is to develop a protocol for single-cell whole genome sequencing of environmental microbes and identify putative full- length antimicrobial gene clusters. Our preliminary data using a controlled mock community demonstrates the feasibility of isolating, lysing, amplification, and sequencing of microbes in high-throughput. Furthermore, we will use a microfluidics approach to select environmental microbes that produce antibiotics that are active against multidrug resistant pathogens. We will also identify corresponding antibiotics-encoding gene cluster from its expression profile using an innovative approach that simultaneously characterizes both DNA and mRNA from a single cell. In Aim 2, we will develop taxa-specific antimicrobials to modulate the microbiome using a prodrug approach. Our initial focus is the phylum Bacteroidetes due to its strong association with a variety of oral and systemic diseases. For example, Porphyromonas gingivalis and periodontitis. Once developed, we will perform in vitro tests using a wide range of pathogens to determine specificity of the antibiotics. Finally, using mice models, we will examine the effect of P. gingivalis inhibition on periodontitis progression. Altogether, the proposed Aims will lay the groundwork for a novel method to discover new, broad-spectrum antibiotics-encoding gene cluster in high-throughput and provide a foundation for microbe-specific targeted therapy.