Small molecule modulation of microbiota: a systems pharmacology perspective

Abstract

Background: Microbes are associated with many human diseases and influence drug efficacy. Small-molecule drugs may revolutionize biomedicine by fine-tuning the microbiota on the basis of individual patient microbiome signatures. However, emerging endeavors in small-molecule microbiome drug discovery continue to follow a conventional “one-drug-one-target-one-disease” process. A systematic pharmacology approach that would suppress multiple interacting pathogenic species in the microbiome, could offer an attractive alternative solution. Results: We construct a disease-centric signed microbe–microbe interaction network using curated microbe metabolite information and their effects on host. We develop a Signed Random Walk with Restart algorithm for the accurate prediction of effect of microbes on human health and diseases. With a survey on the druggable and evolutionary space of microbe proteins, we find that 8–10% of them can be targeted by existing drugs or drug-like chemicals and that 25% of them have homologs to human proteins. We demonstrate that drugs for diabetes can be the lead compounds for development of microbiota-targeted therapeutics. We further show that the potential drug targets that specifically exist in pathogenic microbes are periplasmic and cellular outer membrane proteins. Conclusion: The systematic studies of the polypharmacological landscape of the microbiome network may open a new avenue for the small-molecule drug discovery of the microbiome. We believe that the application of systematic method on the polypharmacological investigation could lead to the discovery of novel drug therapies.