Inhibitor assessment against the LpxC enzyme of antibiotic-resistant Acinetobacter baumannii using virtual screening, dynamics simulation and in vitro assays
Manel Zoghlami,[a] Maroua Oueslati,[a], Zarrin Basharat,[c] Najla Sadfi-Zouaoui [a] and Abdelmonaem Messaoudi*[a,b]
[a] Laboratoire de Mycologie Pathologies et Biomarqueurs (LR16ES05) Département de Biologie Université de Tunis-El Manar 2092 Tunis Tunisie
[b] Higher Institute of Biotechnology of Beja Jendouba University Habib Bourguiba Street 9000 Beja Tunisia
[c] Jamil-ur-Rahman Center for Genome Research Dr. Panjwani Center for Molecular Medicine and Drug Research ICCBS University of Karachi Karachi 75270 Pakistan
*e-mail: email@example.com, phone/fax:0021624321186
Acinetobacter baumannii has been ranked in the list of the World Health Organization as the most critical and priority group of the pathogen for which new antibiotics are urgently needed. A total of 3686 proteins retrieved from the A. baumannii proteome were subjected to subtractive proteomic analysis to narrow down the spectrum of drug targets. The SWISS-MODEL server was used to perform a 3D homology modelling of the selected target protein. The SAVES server was used to evaluate the overall quality of the model. A dataset of 74500 analogues retrieved from the PubChem database was docked with LpxC using the AutoDock software. In this study we predicted a putative new inhibitor for the Lpxc enzyme of A. baumannii. LpxC enzyme was selected as the most appropriate drug target for A. baumannii. Results of virtual screening showed that the N-[(2S)-3-amino-1-(hydroxy amino)-1-oxopropan-2-yl]-4-(4-bromophenyl) benzamide (CS250) could be considered as a promising drug candidate targeting the LpxC enzyme. This molecule shows polar interactions with six amino acids and non-polar interactions with eight other residues. In vitro experimental validation was performed through inhibition assay. The results suggest that CS250 could emerge as a promising inhibitory molecule that can be exploited to target this Gram-negative pathogen.
Keywords: Subtractive proteomics, Acinetobacter baumannii, virtual screening, LpxC, molecular dynamics simulation