Pan-genome derived- Acinetobacter baumannii core drug targets and in vitro evaluation of lead compound “Guanosine 5’

Abstract

Acinetobacter baumannii (A. baumannii), is one of the most common ESKAPE pathogens associated with hospital-acquired nosocomial infections, especially in intensive care units (ICUs). The continuous emergence of multi and extensive drug resistance in A. baumannii widen the challenges to control nosocomial infections. The availability of many completely sequenced genomes of A. baumannii has provided a chance to scrutinize the pangenome of the species along with the pan-phylogeny and the discovery of novel drug targets that could bind with high affinity to drug-like compounds leading to drug discovery. In this context, we explored the pangenome of this concerning pathogen that consist of total 247 complete genome and conducted pangenome analysis and subtractive proteomics. Further, the core proteome (984 proteins) is subjected to subtractive proteomics including subsequent filters (non-human homology, essentiality, virulence, physiochemical checks, and pathways analysis) leading towards the identification of nine broad spectrum potential core drug targets. Additionally, the molecular docking analysis of these drug targets with the FDA Approved and experimental ligands available at the Drug Bank database led to the identification of a total of 6 promising ligands with potential inhibitory effects namely; Cefiderocol, 2-Hydroxyestradiol, 4-chloro-N-(3-methoxypropyl)-N-[(3S)-1-(2-phenylethyl) piperidin-3-yl]benzamide, Uridine-Diphosphate-N-Acetylglucosamine, Guanosine-5'- Monophosphate (GMP), and Dalfopristin. One lead compound GMP was selected for testing antimicrobial activity because of the highest binding affinity with target protein ompR. Antimicrobial susceptibility testing of GMP revealed that this drug did not inhibit the growth of A. baumannii at lower concentrations however detectable inhibition was observed when the drug was used at a higher concentration. The less inhibitory activity of GMP might be due to some cytoplasmic barriers. The lead optimization, del