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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 <jats:italic>E. faecalis<\/jats:italic> 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 <jats:italic>E. faecalis<\/jats:italic> 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 <jats:italic>E. faecalis <\/jats:italic>in vitro. These identified potential HPrK\/P inhibitors open new research avenues towards the development of novel antimicrobials against resistant Gram-positive bacteria.<\/jats:p>","DOI":"10.1007\/s10822-022-00461-6","type":"journal-article","created":{"date-parts":[[2022,7,9]],"date-time":"2022-07-09T04:02:49Z","timestamp":1657339369000},"page":"507-520","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of HPr kinase\/phosphorylase inhibitors: novel antimicrobials against resistant Enterococcus faecalis"],"prefix":"10.1007","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5209-0277","authenticated-orcid":false,"given":"Sandeep","family":"Kumar","sequence":"first","affiliation":[]},{"given":"Rajendra","family":"Bhadane","sequence":"additional","affiliation":[]},{"given":"Shruti","family":"Shandilya","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-126X","authenticated-orcid":false,"given":"Outi M. 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