INHIBITION OF PEPTIDOGLYCAN BIOSYNTHESIS IN VANCOMYCIN-SUSCEPTIBLE AND VANCOMYCIN-RESISTANT BACTERIA BY A SEMISYNTHETIC GLYCOPEPTIDE ANTIBIOTIC

LY191145 is a p-chlorobenzyl derivative of LY264826 (A82846B) with act ivity against both vancomycin-susceptible and -resistant enterococci, Incorporation of L-[C--14]lysine into peptidoglycan of intact vancomyc in-susceptible and -resistant Enterococcus faecium was inhibited by LY 191145 (50% inhibitory concentrations of 1 and 5 mu g/ml, respectively ). Inhibition was accompanied by accumulation of UDP-muramyl-peptide p recursors in the cytoplasm, This agent inhibited late-stage steps in p eptidoglycan biosynthesis in permeabilized E. faecium when either the UDP-muramyl-pentapeptide precursor from vancomycin-susceptible E, faec ium or the UDP-muramyl-pentadepsipeptide precursor from vancomycin-res istant E. faecium was used as a substrate. Inhibition of late-stage st eps led to accumulation of an N-acetyl-[C-14] glucosamine-labeled lipi d intermediate indicative of inhibition of the transglycosylation step , Inhibition of peptidoglycan polymerization without affecting cross-l inking in a particulate membrane-plus-wall-fragment assay from Aerococ cus viridans was consistent with this explanation, The fact that inhib ition of peptidoglycan biosynthesis by LY191145 was not readily antago nized by an excess of free acyl-D-alanyl-D-alanine or acyl-D-alanyl-D- lactate ligands indicates that the manner in which this compound inhib its transglycosylation may not be identical to that of vancomycin.