Identification of HPr kinase/phosphorylase inhibitors: novel antimicrobials against resistant Enterococcus faecalis
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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2022-07
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en
Pages
14
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Journal of Computer-Aided Molecular Design, Volume 36, issue 7, pp. 507-520
Abstract
Enterococcus faecalis, a gram-positive bacterium, is among the most common nosocomial pathogens due to its limited susceptibility to antibiotics and its reservoir of the genes coding for virulence factors. Bacterial enzymes such as kinases and phosphorylases play important roles in diverse functions of a bacterial cell and, thus, are potential antibacterial drug targets. In Gram-positive bacteria, HPr Kinase/Phosphorylase (HPrK/P), a bifunctional enzyme is involved in the regulation of carbon catabolite repression by phosphorylating/dephosphorylating the histidine-containing phosphocarrier protein (HPr) at Ser46 residue. Deficiencies in HPrK/P function leads to severe defects in bacterial growth. This study aimed at identifying novel inhibitors of E. faecalis HPrK/P from a commercial compound library using structure-based virtual screening. The hit molecules were purchased and their effect on enzyme activity and growth of resistant E. faecalis was evaluated in vitro. Furthermore, docking and molecular dynamics simulations were performed to study the interactions of the hit compounds with HPrK/P. Among the identified hit molecules, two compounds inhibited the phosphorylation of HPr as well as significantly reduced the growth of resistant E. faecalis in vitro. These identified potential HPrK/P inhibitors open new research avenues towards the development of novel antimicrobials against resistant Gram-positive bacteria.Description
Funding Information: This research was supported by funds from the ICAR-National Dairy Research Institute and a fellowship awarded by the Council of Scientific & Industrial Research, India (Suman Kapila and Sandeep Kumar) and by the Åbo Akademi University research mobility programme within the research profiling area “Drug Development and Diagnostics” (R.B.). The Sigrid Jusélius Foundation, Biocenter Finland Bioinformatics and Drug Discovery and Chemical Biology networks, CSC IT Center for Science, Joe, Pentti and Tor Borg Memorial Fund and Prof. Mark Johnson and Dr. Jukka Lehtonen are gratefully acknowledged for the excellent computational infrastructure at the Åbo Akademi University. This work contributes also to the activities within the strategic research profiling area Solutions for Health at Åbo Akademi University (Academy of Finland, # 336355). Publisher Copyright: © 2022, The Author(s).
Keywords
E. faecalis, HPr, HPrK/P, Molecular docking, Molecular dynamics simulation, Structure-based drug design, Virtual screening
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Citation
Kumar, S, Bhadane, R, Shandilya, S, Salo-Ahen, O M H & Kapila, S 2022, ' Identification of HPr kinase/phosphorylase inhibitors : novel antimicrobials against resistant Enterococcus faecalis ', Journal of Computer-Aided Molecular Design, vol. 36, no. 7, pp. 507-520 . https://doi.org/10.1007/s10822-022-00461-6