An antibiotic target ranking and prioritization pipeline combining sequence, structure and network-based approaches exemplified for Serratia marcescens

摘要

We investigate a drug target screening pipeline comparing sequence, structure and network-based criteria for prioritization. Serratia marcescens, an opportunistic pathogen, serves as test case. We rank according to (i) availability of three dimensional structures and lead compounds, (ii) not occurring in man and general sequence conservation information, and (iii) network information on the importance of the protein (conserved protein-protein interactions; metabolism; reported to be an essential gene in other organisms). We identify 45 potential anti-microbial drug targets in S. marcescens with KdsA involved in LPS biosynthesis as top candidate drug target. LpxC and FIgB are further top-ranked targets identified by interactome analysis not suggested before for S. marcescens. Pipeline, targets and complementarity of the three approaches are evaluated by available experimental data and genetic evidence and against other antibiotic screening pipelines. This supports reliable drug target identification and prioritization for infectious agents (bacteria, parasites, fungi) by these bundled complementary criteria. (C) 2016 Elsevier B.V. All rights reserved.