ANTI-VIRULENCE STRATEGIES TO COMBAT MDR PSEUDOMONAS AERUGINOSA: IN SILICO SCREENING TO TARGET QUORUM SENSING AS A SUBSTITUTION FOR CONVENTIONAL ANTIBIOTICS.

Abstract

Pseudomonas aeruginosa is a member of the world health organization’s (WHO) ESKAP group and critical priority list because treating MDR (Multidrug-Resistant) Pseudomonas aeruginosa infections are clinically more exigent these days. Conventional antibiotics such as beta-lactams, carbapenems, and fluoroquinolones applies fatal force on bacteria that causes brisk mutations for survival producing Anti-microbial resistance (AMR). The pathogen evades host immune system by using enzymes such as elastase and protease that act as virulence factors, these factors are released by pathogen’s biofilm that is formed via cell density dependent microbial communication system called Quorum sensing. This thesis explores a fundamentally different strategy that is anti-virulence therapy, in which the bacteria are not killed, but rather their survival is disrupted. We targeted the LasR-QslA complex (PDB ID: 4NG2), which is the master regulator of the las quorum sensing system of P. aeruginosa. An in-silico virtual screening campaign was conducted in which 2,500 natural phytochemicals were screened using PyRx-integrated AutoDock Vina.and pharmacokinetic safety profiling was performed using the SwissADME web server, and binding interactions were analysed in the BIOVIA Discovery Studio Visualizer. Screening results identified Glomeremophilane B (PubChem CID: 139589801) as the lead compound, with a binding affinity of −7.9 kcal/mol. It is 2.7 kcal/mol better than the native autoinducer 3-oxo-C12-HSL (−5.2 kcal/mol) and 2.4 kcal/mol superior to the validated reference beta-caryophyllene (−5.5 kcal/mol). Interaction analysis revealed that Glomeremophilane B forms 6 hydrogen bonds with TRP75, TRP76, THR76, and GLN103 residues that is a dense polar engagement pattern that predicts high binding stability. SwissADME profiling confirmed: high GI absorption, zero CYP isoform inhibition, no BBB penetration, and full Lipinski's Rule of Five compliance. All these together establish Glomeremophilane B as a clinically relevant anti-virulence lead compound.