Small Molecule Modulation of Microbiome Ecosystem: A Systems Pharmacology Perspective

An increasing body of evidence suggests that microbes are not only strongly associated with many human diseases but also responsible for the efficacy, resistance, and toxicity of drugs. Small-molecule drugs which can precisely fine-tune the microbial ecosystem on the basis of individual patients may revolutionize biomedicine. However, emerging endeavors in small-molecule microbiome drug discovery continue to follow a conventional "one-drug-one-target-one-disease" process. It is often insufficient and less successful in tackling complex systematic diseases. A systematic pharmacology approach that intervenes multiple interacting pathogenic species in the microbiome, could offer an attractive alternative solution. Advances in the Human Microbiome Project have provided numerous genomics data to study microbial interactions in the complex microbiome community. Integrating microbiome data with chemical genomics and other biological information enables us to delineate the landscape for the small molecule modulation of the human microbiome network. In this paper, we construct a disease-centric signed microbe-microbe interaction network using metabolite information of microbes and curated microbe effects on human health from published work. We develop a Signed Random Walk with Restart algorithm for the accurate prediction of pathogenic and commensal species. 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 also demonstrate that drugs for diabetes are enriched in the potential inhibitors that target pathogenic microbe without affecting the commensal microbe, thus can be repurposed to modulate the microbiome ecosystem. We further show that periplasmic and cellular outer membrane proteins are overrepresented in the potential drug targets set in pathogenic microbe, but not in the commensal microbe. The systematic studies of polypharmacological landscape of the microbiome network may open a new avenue for the small-molecule drug discovery of microbiome.