Class II HMG-CoA Reductase Inhibitors targeting Methicillin-Resistant Staphylococcus pseudintermedius

Abstract

Staphylococcus pseudintermedius is a component of the normal flora of companion animals that contributes to opportunistic infections in dogs. Clinical isolates of S. pseudintermedius (chiefly methicillin-resistant S. pseudintermedius (MRSP)) have been identified that exhibit resistance to nearly all antibiotic classes. There is a need for new antibiotics that target novel pathways within resistant pathogens such as MRSP. A possible novel antibacterial target in Gram-positive cocci is class II HMG-CoA reductase (HMGR), a key enzyme present in the mevalonate pathway that is essential for bacterial survival. In this study we examined novel synthetic compounds that are potent inhibitors of bacterial HMGRs. The compounds inhibited growth, in low micromolar concentration, of clinical isolates of methicillin-sensitive S. pseudintermedius (MSSP) and MRSP via the broth microdilution assay. The MTS assay confirmed the most potent compound (6) wasnot toxic to different mammalian cell lines (up to 128 µM). A time-kill assay revealed this compound rapidly eradicates a high inoculum of MRSP within two hours. This study provides evidence that compound 6 is a promising agent that warrants further investigation as a novel treatment option for MRSP infections.