English

Abstract

Enterobacter cloacae is a clinically significant Gram-negative, facultatively-anaerobic, rod-shaped bacterium belonging to the family of Enterobacteriaceae. It has emerged as a prevalent nosocomial pathogen due to high level resistance to disinfec- tants and antimicrobial agents. The availability of complete genome sequence of E. cloacae has paved the new way to identify the novel drug targets. In the present work comparative analysis of the metabolic pathways of the pathogen and host was performed to identify the novel drug targets involved in pathogen but absent in Homo sapiens. All enzymes involved in the metabolic pathways of E. cloacae were searched against the proteome of H. sapiens using the BLASTp program. The threshold of percentage identity was set to as 0.001, and the query coverage < 50. Using these parameters approximately 44 unique putative targets were identified. Out of those non-homologous targets, 22 coding genes for putative targets were identified as essential genes from the DEG database. Based on extensive literature search, 8 targets such as UDP-N-acetylmuramoyl-L-alanyl-D-gluta- mate synthetase, UDP-N-acetylmuramate-L-alanine ligase, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-2, 6-diaminopimelate ligase, UDP-N-acetylmuramoyl-tripeptide-D-alanyl-D-alanine ligase, UDP-N-acetylmuramate-L-alanine ligase (MurC) α-isopro- pylmalate synthase, UDP-N-Acetylglucosamine Enolpyruvyl Transferase, UDP-N-acetylenolpyruvylglucosamine reductase and Aspartate beta-semialdehyde dehydrogenase were identified as potential drug targets. Among these drug targets, UDP-N-acetylmu - ramate-L-alanine ligase (MurC) was chosen as potential therapeutic drug target. The homology modeling of MurC was performed using SWISS-MODEL and HHPred servers respectively. Subsequently, all the predicted models were evaluated using the SAVES server. The stereochemical parameters of all 3D models suggest that the best model was predicted by HHPred server. In order the refine the modeled structure, energy minimization was also performed using Deep View tool. The refined 3D structure was further validated by ProSA server. In future, the 3D structure of MurC in E. cloacae might be exploited for the discovery of novel inhibitors that could potentially inhibit this nosocomial pathogen.