title: Further investigation of inhibitors of MRSA pyruvate kinase: Towards the conception of novel antimicrobial agents.
abstract: Several novel series of compounds were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK has been identified as a highly interconnected essential 'hub' protein in MRSA, with structural features distinct from the human homologs which makes it a novel antimicrobial target. Several MRSA PK inhibitors (including the hydrazide 1) were identified using in silico screening combined with enzyme assays and were found to be selective for bacterial enzyme compared to human PK isoforms. Structure-activity relationship (SAR) studies were carried out on the replacement of the hydrazide linker with 3-atoms, 2-atoms and 0-atom linkers and led us to discover more potent compounds with enzyme inhibiting activities in the low nanomolar range and some were found to effectively inhibit bacteria growth in culture with minimum inhibitory concentrations (MIC) as low as 1 μg/mL.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. Electronic address: christophe.labriere@gmail.com.
authors.forename: Christophe
authors.initials: C
authors.lastname: Labrière
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Huansheng
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: B Brett
authors.initials: BB
authors.lastname: Finlay
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada; Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Reiner
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. Electronic address: roberty@sfu.ca.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Young
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D003198:Computer Simulation; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology*; D008826:Microbial Sensitivity Tests; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011770:Pyruvate Kinase
keywords: Antimicrobial; Methicillin-resistant Staphylococcus aureus; Pyruvate kinase inhibitor; Structure–activity relationships