Acinetobacter baumannii is considered a threat to global health due to the emerging and constantly increasing resistance of the organism to conventional antibiotics through biofilm formation. Biofilm formation in A. baumannii is activated majorly by the AbaI/AbaR quorum sensing system (QSS), thus the discovery and development of anti-AbaR is imperative. In this study, phenolics (due to their significant antibacterial properties) were repurposed as modulator of AbaR of A. baumannii using computational techniques. The top five anti-AbaR phenolics were identified through structure-activity-based screening, pharmacokinetics, and synthetic feasibility assessments before being subjected to 200 ns molecular dynamics simulations for further thermodynamic refinement and evaluation. The top five phenolics had higher binding free energy than the two standards, tetracycline (-27.55 kcal/mol) and kaempferol (-33.99 kcal/mol) with ZINC08552019 (-46.58 kcal/mol) having the best affinity towards the protein. The thermodynamic findings also suggest greater stability of AbaR following binding of the top five phenolics with ZINC63492410 (2.21 Å) being the most stable. This observation is indicative of the anti-AbaR potential of the top five phenolics and most especially ZINC08552019. Further quantum calculations of the top five phenolics using DFT/B3LYP revealed that ZINC08552019 had a significant ionization potential energy and electron affinity that is suggestive of its superior potential to attract electrons from the active site of AbaR. These results are not only in tandem with the thermodynamic findings but further profile ZINC08552019 as a probable drug candidate against resistant A. baumannii through its modulatory role on the AbaR QSS. The lead compound (ZINC08552019) is currently the subject of additional confirmatory in vitro studies.
Keywords: Quorum sensing, Acinetobacter baumannii, AbaR, Phenolics, Molecular dynamics simulation