Translational protein RpsE as an alternative target for novel nucleoside analogues to treat MDR Enterobacter cloacae ATCC 13047: network analysis and molecular dynamics study

Abstract

The pathogenic Enterobacter cloacae subsp. cloacae str. ATCC 13047 has contemporarily emerged as a multi-drug resistant strain. To formulate an effective treatment option, alternative therapeutic methods need to be explored. The present study focused on Gene Interaction Network study of 46 antimicrobial resistance genes to reveal the densely interconnecting and functional hub genes in E. cloacae ATCC 13047. The AMR genes were subjected to clustering, topological and functional enrichment analysis, revealing rpsE (RpsE), acrA (AcrA) and arnT (ArnT) as novel therapeutic drug targets for hindering drug resistance in the pathogenic strain. Network topology further indicated translational protein RpsE to be exploited as a promising drug-target candidate for which the structure was predicted, optimized and validated through molecular dynamics simulations (MDS). Absorption, distribution, metabolism and excretion screening recognized ZINC5441082 ( N -Isopentyladenosine) (Lead_1) and ZINC1319816 (cyclopentyl-aminopurinyl-hydroxymethyl-oxolanediol) (Lead_2) as orally bioavailable compounds against RpsE. Molecular docking and MDS confirmed the binding efficacy and protein−ligand complex stability. Furthermore, binding free energy (G bind ) calculations, principal component and free energy landscape analyses affirmed the predicted nucleoside analogues against RpsE protein to be comprehensively examined as a potential treatment strategy against E. cloacae ATCC 13047. Supplementary information The online version contains supplementary material available at 10.1007/s11274-023-03634-z.

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