3t07

Publication Abstract from PubMed

Novel classes of antimicrobials are needed to address the emergence of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). We have recently identified pyruvate kinase (PK) as a potential novel drug target based upon it being an essential hub in the MRSA interactome (1,2). Screening of an extract library of marine invertebrates against MRSA PK resulted in the identification of bis-indole alkaloids of the spongotine (A), topsentin (B, D) and hamacanthin (C) classes isolated from the Topsentia pachastrelloides as novel bacterial PK inhibitors. These compounds potently and selectively inhibited both MRSA PK enzymatic activity and S. aureus growth in vitro. The most active compounds cis-3,4-dihyrohyrohamacanthin B (C) and bromodexytopsentin (D) were identified as highly potent MRSA PK inhibitors (IC50 values of 16-60 nM) with at least 166-fold selectivity over human PK isoforms. These novel anti-PK natural compounds exhibited significant antibacterial activities against S. aureus, including MRSA (MICs of 12.5 and 6.25 mug/ml, respectively) with selectivity indices (CC50/MIC) > 4. We also report the discrete structural features of the MRSA PK tetramer as determined by X-ray crystallography, which is suitable for selective targeting of the bacterial enzyme. The co-crystal structure of compound C with MRSA PK confirms that the latter is a target for bis-indole alkaloids. It elucidates the essential structural requirements for PK inhibitors in small interfaces that provide for tetramer rigidity and efficient catalytic activity. Our results identified a series of natural products as novel MRSA PK inhibitors, providing the basis for further development of potential novel antimicrobials.

MRSA pyruvate kinase as a target for bis-indole alkaloids with antibacterial activities.,Zoraghi R, Warroll L, See RH, Strangman W, Popplewell WL, Gong H, Samaai T, Swayze RD, Kaur S, Vuckovic M, Finlay BB, Brunham RC, McMaster WR, Davies-Coleman MT, Strynadka NC, Andersen RJ, Reiner NE J Biol Chem. 2011 Oct 26. PMID:22030393^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.