To combat the emergence of drug-resistant bacterial pathogens such as Methicillin-Resistant Staphylococcus Aureus (MRSA) and Vancomycin-Resistant Enterococcus (VRE) as serious threats to human health, a new class of antimicrobials that target the Class II HMG-CoA Reductase (HMGR) enzyme found in Gram-positive cocci has been developed. A lead HMGR inhibitor (1  ) discovered in a screen of a 30,000-member library was co-crystallized with HMGR and the crystal structure thus obtained was used as the basis for structure-based modifications to the original structure. Of the fourteen analogues initially synthesized, three (2-4  ) were identified that displayed both potent in vitro inhibition of HMGR and potent antimicrobial activity against MRSA and VRE.  Inhibitors 2-4   have been shown to have activity against clinical isolates of MRSA and VRE and against biofilms. They have also been shown to display selectivity for the Gram-positive pathogens as they do not affect the Gram negative bacterium E. coli. Inhibitors 2-4   also display no cytotoxicity toward cultured murine cells at a concentration an order of magnitude greater than their IC50 values. Inhibitors 2-4   have also been tested in a C. elegans model of infection. When tested at 100 mM concentration, inhibitors 2-4   were found to be 10-fold more effective at killing bacteria in C. elegans than the clinically used antibiotics vancomycin and linezolid tested at comparable concentration. Co-crystal structures of 2-4 with HMGR have been obtained and show that these inhibitors bind into the active in the same region as the substrate, making polar contact with a number of key active site residues. Prospects for more potent and selective HGMR inhibitors will also be discussed.

Structure-based design of HMG CoA reductase inhibitors as novel antimicrobials targeting drug resistant bacterial pathogens

248th National Meeting (2014)

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