Small molecule modulation of microbiota: a systems pharmacology perspective

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.

Automated summary

This study constructed a disease-centric microbial interaction network and developed an accurate algorithm for predicting the effects of microbes on human health and diseases. The study found potential drug targets in microbial proteins and demonstrated that pathogenic microbes have specific drug targets in periplasmic and cellular outer membrane proteins. This research opens a new avenue for the small-molecule drug discovery of the microbiome.