Cheminformatics identification of phenolics as modulators of key penicillin−binding proteins of Escherichia coli towards interventive antibacterial therapy

Abstract

ABSTRACT Data implicating the mutation in penicillin-binding protein (PBP) 3 and occasionally PBP5 in the resistance of Escherichia coli to beta−lactams is intriguing. Thus, the identification of an improved class of inhibitors of PBP3 and PBP5 is imperative, and in this study, phenolics due to their promising antibacterial activities were screened using structure−based pharmacophore and molecular docking approaches against PBP3, and the ability of the lead phenolics to modulate PBP3 and PBP5 was studied using molecular dynamics simulation. The results demonstrated various inhibitory capacities of the lead phenolics, with lysidicichin (−41.66 kcal/mol) and silicristin (−31.11 kcal/mol) being the most potent against PBP3, while epicatechin 3-O-(3-O-methylgallate) (−38.97 kcal/mol) and epigallocatechin-4-benzyl thioether (−37.01 kcal/mol) had higher affinities towards PBP5. Overall, epicatechin gallate had the best broad-spectrum of activity, as the compound was able to bind favourably to both targets. Additionally, the thermodynamic information confirmed the stability of the lead phenolics with both targets. Conclusively, while these observations are suggestive of the modulatory role of the lead phenolics on the growth of E. coli, further in vitro and in vivo validation of the activity elicited by the phenolics in this study is imperative, and efforts are underway in this direction.