MraY translocase inhibitors

The first step in the membrane cycle of reactions during peptidoglycan biosynthesis is the transfer of phospho-MurNAc-pentapeptide from UDP-MurNAc-pentapeptide to undecaprenyl phosphate, catalyzed by the integral membrane protein phospho-MurNAc-pentapeptide translocase (also referred to as MraY translocase).

Different translocase I inhibitors have been discovered. Caprazamycins (CPZs) are liponucleoside antibiotics isolated from Streptomyces sp. MK730-62F2 (22). They possess activity in vitro against Gram-positive bacteria, in particular against the genus Mycobacterium including M. intracellulare, M. avium and M. tuberculosis. Structural elucidation (9) revealed a complex and unique composition of moieties the CPZs share only with the liposidomycins (LPMs) (14). The core skeleton is the (+)-caprazol composed of an N-alkylated α-(5’’-(β-1-O-aminoribosyl)-uridinyl-glycine which is cyclized to form a rare diazepanone ring. Attached to the 3’’’-OH are ß-hydroxy-fatty acids of different chain length resulting in CPZs A - G. They differ from the LPMs by the absence of a sulfate group at the 2’’-position of the aminoribose and the presence of a permethylated L-rhamnose glycosidically linked to the 3-methylglutaryl (3-MG) moiety.

Mureidomycins (MRDs) were isolated from Streptomyces flavidoviridens SANK60486 (10-13). They are active against Pseudomonas strains and protected mice against P. aeruginosa infection. MRDs A – D are uridylpeptide natural products containing a 3-deoxyuridine sugar attached via an enamide linkage to a peptide chain. MRDs C and D contain an additional glycine residue at the amino terminus, while B and D contain dihydrouracil in place of uracil. MRD A selectively inhibits bacterial MraY translocase, showing no inhibition of bacterial teichoic acid or mammalian glycoprotein biosynthesis. MRD A showed time-dependent inhibition of solubilised E. coli translocase I, and was found to be a slow-binding inhibitor. Closely related to the MRDs are the pacidamycins (PACs) (2, 4, 15) and napsamycins (NPSs) (1). Both have similar activities against Pseudomonas sp., but did not protect mice against P. aeruginosa infection.