title: Discovery and optimization of a new class of pyruvate kinase inhibitors as potential therapeutics for the treatment of methicillin-resistant Staphylococcus aureus infections.
abstract: A novel series of bis-indoles derived from naturally occurring marine alkaloid 4 were synthesized and evaluated as inhibitors of methicillin-resistant Staphylococcus aureus (MRSA) pyruvate kinase (PK). PK is not only critical for bacterial survival which would make it a target for development of novel antibiotics, but it is reported to be one of the most highly connected 'hub proteins' in MRSA, and thus should be very sensitive to mutations and making it difficult for the bacteria to develop resistance. From the co-crystal structure of cis-3-4-dihydrohamacanthin B (4) bound to S. aureus PK we were able to identify the pharmacophore needed for activity. Consequently, we prepared simple direct linked bis-indoles such as 10b that have similar anti-MRSA activity as compound 4. Structure-activity relationship (SAR) studies were carried out on 10b and led us to discover more potent compounds such as 10c, 10d, 10k and 10 m with enzyme inhibiting activities in the low nanomolar range that effectively inhibited the bacteria growth in culture with minimum inhibitory concentrations (MIC) for MRSA as low as 0.5 μg/ml. Some potent PK inhibitors, such as 10b, exhibited attenuated antibacterial activity and were found to be substrates for an efflux mechanism in S. aureus. Studies comparing a wild type S. aureus with a construct (S. aureus LAC Δpyk::Erm(R)) that lacks PK activity confirmed that bactericidal activity of 10d was PK-dependant.
authors: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
authors: Nag S
authors: NS
authors: Kumar
authors: Centre for Drug Research and Development (CDRD), Vancouver, BC, Canada.
authors: Edie M
authors: EM
authors: Dullaghan
authors: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada.
authors: B Brett
authors: BB
authors: Finlay
authors: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada.
authors: Huansheng
authors: H
authors: Gong
authors: 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: Neil E
authors: NE
authors: Reiner
authors: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
authors: J
authors: J
authors: Jon Paul Selvam
authors: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada.
authors: Lisa M
authors: LM
authors: Thorson
authors: Centre for Drug Research and Development (CDRD), Vancouver, BC, Canada.
authors: Sara
authors: S
authors: Campbell
authors: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Nicholas
authors: N
authors: Vitko
authors: Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: Anthony R
authors: AR
authors: Richardson
authors: Department of Medicine, Division of Infectious Diseases, University of British Columbia, Vancouver, BC, Canada.
authors: Roya
authors: R
authors: Zoraghi
authors: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada. Electronic address: robert_young@sfu.ca.
authors: Robert N
authors: RN
authors: Young
mesh_terms: D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000737:chemistry* / Q000302:isolation & purification; D015394:Molecular Structure; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D013203:Staphylococcal Infections / Q000382:microbiology; D013329:Structure-Activity Relationship
chemical_list: D011770:Pyruvate Kinase
keywords: Antibacterial; Bis-indole; MRSA; Pyruvate kinase