Small Molecule Modulation of Microbiome Ecosystem: A Systems Pharmacology Perspective

Abstract

21 An increasing body of evidence suggests that microbes are not only strongly associated with many 22 human diseases but also responsible for the efficacy, resistance, and toxicity of drugs. Small-23 molecule drugs which can precisely fine-tune the microbial ecosystem on the basis of individual 24 patients may revolutionize biomedicine. However, emerging endeavors in small-molecule 25 microbiome drug discovery continue to follow a conventional "one-drug-one-target-one-disease" 26 process. It is often insufficient and less successful in tackling complex systematic diseases. A 27 systematic pharmacology approach that intervenes multiple interacting pathogenic species in the 28 microbiome, could offer an attractive alternative solution. Advances in the Human Microbiome 29 Project have provided numerous genomics data to study microbial interactions in the complex 30 microbiome community. Integrating microbiome data with chemical genomics and other 31 biological information enables us to delineate the landscape for the small molecule modulation of 32 the human microbiome network. In this paper, we construct a disease-centric signed microbe-33 microbe interaction network using metabolite information of microbes and curated microbe effects 34 on human health from published work. We develop a Signed Random Walk with Restart algorithm 35 for the accurate prediction of pathogenic and commensal species. With a survey on the druggable 36 and evolutionary space of microbe proteins, we find that 8-10% of them can be targeted by existing 37 drugs or drug-like chemicals and that 25% of them have homologs to human proteins. We also 38 demonstrate that drugs for diabetes are enriched in the potential inhibitors that target pathogenic 39 microbe without affecting the commensal microbe, thus can be repurposed to modulate the 40 microbiome ecosystem. We further show that periplasmic and cellular outer membrane proteins 41 are overrepresented in the potential drug targets set in pathogenic microbe, but not in the 3 42 commensal microbe. The systematic studies of polypharmacological landscape of the microbiome 43 network may open a new avenue for the small-molecule drug discovery of microbiome.