Identifying a Vaginal Microbiome-Derived Selective Antibiotic Metabolite via Microbiome Pharmacology Analysis.

The vaginal microbiome plays a critical role in maintaining immune and epithelial homeostasis in the female reproductive tract. Bacterial Vaginosis (BV) is deleterious to female health, causing the loss of beneficial species, overgrowth of anaerobic taxa, changes in vaginal pH, breakdown of protective mucins and epithelial barriers, and activation of the immune system. Treatment with gel-based antibiotics (Metronidazole or Clindamycin) resolves BV for 85% of patients, but 50% of those cases recur, indicating a need to identify strategies for overcoming antibiotic resistance and achieving a more durable response. Here, we developed a systems biology approach termed to characterize the antibiotic potential of vaginal microbes, their metabolites and functions, via computational fusion of human cohort multi-omics and post-drug perturbation transcriptomic profiles. We focused on Clindamycin and Metronidazole as candidate drugs and screened 780 vaginal microbiome-drug mimicry candidates to identify candidate taxa and metabolites with antibiotic potential. We demonstrate experimentally that -derived Hydroxyisocaproate (HICA) selectively kills and that HICA enhances epithelial barrier integrity in a human vagina-on-a-chip system. Our work demonstrates the first use of , for discovering novel, selective antibiotic metabolites for BV with implications for charting the full pharmacologic potential of the vaginal microbiome.