3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMG-CoA synthase) (HMGCS)

Bacterial 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase is a critical enzyme in the mevalonate pathway, which is essential for the survival of several major Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis (PubMed: 15131257). The enzyme catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to produce HMG-CoA, a precursor for isoprenoid biosynthesis. Isoprenoids are necessary for the production of cell wall components like undecaprenyl phosphate and respiratory chain elements like menaquinone. Because many other bacteria use the alternative MEP pathway, this enzyme represents a selective target for specific antibiotic intervention. Small molecule inhibitors, such as the beta-lactone hymeglusin, have been shown to covalently bind to the catalytic cysteine residue (Cys111 in S. aureus), effectively halting bacterial growth (PubMed: 11071306). The primary therapeutic challenge lies in achieving high selectivity over human HMG-CoA synthase isoforms (HMGCS1 and HMGCS2) to avoid interfering with host cholesterol synthesis and ketone body production (PubMed: 24508300). Structural studies have identified unique pockets in the bacterial enzyme that may allow for the design of highly specific inhibitors. Consequently, bacterial HMG-CoA synthase is a high-priority target for the development of novel classes of antibiotics to combat multidrug-resistant infections.

Other names

3-hydroxy-3-methylglutaryl-CoA synthasemvaSHydroxymethylglutaryl-CoA synthaseHMGSHMG-CoA synthase

Covalent inhibition of the active site cysteine residue, which prevents the condensation of acetyl-CoA and acetoacetyl-CoA into HMG-CoA (PubMed: 11071306).