Unravelling the Design and Mechanism: Potential of Substituted Quinolines as PASTA subunit 4 Inhibitors for Antimicrobial Activity

Abstract

AbstractThe increasing incidences of antibiotic‐resistance in Microorganisms have become a critical global health challenge. Traditional treatments, often relying on multiple antibiotics, are plagued by issues like drug resistance, reduced effectiveness, and heightened toxicity. In response, there is a compelling demand for innovative anti‐microbial agents that offer novel mechanisms of action. The family of bacterial Penicillin‐binding protein And Serine/Threonine kinase‐Associated (PASTA) kinases is of particular interest due to the role of these kinases in regulating resistance to ‐lactam antibiotics. As such, small molecule kinase inhibitors that target PASTA kinases may prove beneficial as treatments adjunctive to ‐lactam therapy. Our study was primarily geared towards identifying novel PASTA Kinase inhibitors through a ligand‐based drug design approach. Subsequently, we curated a library of 12 molecules, incorporating chemical modifications guided by considerations like drug‐like properties, chemical accessibility, and synthetic feasibility. Molecular docking analyses conducted on this library pinpointed three molecules with noteworthy binding affinities. From this subset, KS_QD_04 and KS_QD_05 emerged as promising candidates, subsequently validated through MD simulation studies, bolstering their potential as lead compounds in the quest to develop PASTA Kinase inhibitors for combating raising microbial resistance towards antibiotics.