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Eur J Med Chem. 2017 Jan 5;125:1-13. doi: 10.1016/j.ejmech.2016.09.018. Epub 2016 Sep 9.

Further investigation of inhibitors of MRSA pyruvate kinase: Towards the conception of novel antimicrobial agents.

Author information

1
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. Electronic address: christophe.labriere@gmail.com.
2
Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada.
3
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.
4
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.
5
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. Electronic address: roberty@sfu.ca.

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.

KEYWORDS:

Antimicrobial; Methicillin-resistant Staphylococcus aureus; Pyruvate kinase inhibitor; Structure–activity relationships

PMID:
27643559
DOI:
10.1016/j.ejmech.2016.09.018
[Indexed for MEDLINE]

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