Screening for Microbial Therapeutic Interactions in Malignancy

Bacteria comprising the human gut microbiome have been linked to a myriad of health outcomes, including response to cancer treatment. Although an association between the microbiome and chemotherapeutic agents is well established, mechanisms underlying “bug-drug” interactions remain poorly understood. In large part, this is due to bacterial strain-level variation, as well as the difficulty of identifying and isolating strains that interact with chemotherapeutics from the larger gastrointestinal bacterial community. We hypothesized that improved bacterial growth in the presence of cancer therapeutics is a valid marker of a significant bacterial-drug interaction. To this end, we have developed a novel microbe-centric screening method to identify and isolate bacterial strains in human microbiomes that interact with cancer agents of interest, with the ultimate goal of identifying the bacterial genetic elements responsible for the observed growth shifts. In preliminary studies, over forty therapeutics have been screened in three different human microbiota. Our results suggest that select agents have a reproducible and significant growth impact, driven by previously unknown antimicrobial effects, on a subset of microbial strains. We have successfully isolated sensitive and resistant strains of interest from human microbiota; comparative genomic, transcriptomic, and directed evolution studies to identify relevant genetic elements are ongoing. If successful, this work could result in the identification of novel pathways in the antibiotic resistome that carry meaningful implications in the context of cancer treatment, and which could be leveraged more broadly in future efforts to engineer the gut microbiome. More broadly, our microbiome screening pipeline may be applied to a range of drug classes to allow for discovery of not only genetic response mechanisms, but also identification of regulators of gene expression. These xenobiotic compounds could be repurposed as chemical modulators for programmable induction or repression of gene expression of gut bacteria in future bioengineering and synthetic biology applications.