Synthesis of Class II HMG-CoA Reductase Inhibitors: As New Potent Nosocomial Antibiotics

Antibiotic resistant pathogenic bacteria such as vancomycin resistant Enterococcus (VRE) and methicillin resistant Staphylococcus aureus (MRSA) are the most common causes of infections in U.S. and European hospitals. These are known to be hospital-acquired infections, also called nosocomial infections, which appear within the first 48 hours or more after hospital admission. Previous studies report that Gram positive bacteria such as these pathogens use the mevalonate pathway for isopentenyl diphosphate biosynthesis in their cell wall biosynthesis. Class II HMG-CoA reductase (II-HMGCR) converts HMG-CoA to mevalonate and is one of the main enzymes in the mevalonate pathway for these bacteria. Inhibition of II-HMGCR represents a potential antibacterial strategy for nosocomial pathogenic bacteria.  The aryl sulfonamide 5-(N-(4-butylphenyl)sulfamoyl)-2-hydroxybenzoic acid (N-bsha) was found to inhibit Enterococcus faecalis II-HMGCR with an IC₅₀ of 5 µM.  X-ray crystallographic studies reveal that this compound binds in the active site of E. faecalis II-HMGCR.  Herein we present the rational design and synthesis of II-HMGCR inhibitory analogues of N-bsha.  Analogues were obtained in high yields and with 70-99% purity, as determined by HPLC. Enzymatic inhibition of E. faecalis and S. aureus II-HMGCR by these new analogues resulted in IC₅₀ values from 0.181 to 4.6 mM.  The present study provides a new class of potential antibiotics scaffolds for the selective treatment of MRSA and VRE infections.