Novel FR-900493 Analogues That Inhibit the Outgrowth of Spores.

The spectrum of antibacterial activity for the nucleoside antibiotic FR-900493 () can be extended by chemical modifications. We have generated a small focused library based on the structure of and identified UT-17415 (), UT-17455 (), UT-17460 (), and UT-17465 (), which exhibit anti- growth inhibitory activity. These analogues also inhibit the outgrowth of spores at 2× minimum inhibitory concentration. One of these analogues, , relative to exhibits over 180-fold and 15-fold greater activity against the enzymes, phospho-MurNAc-pentapeptide translocase (MraY) and polyprenyl phosphate-GlcNAc-1-phosphate transferase (WecA), respectively. The phosphotransferase inhibitor displays antimicrobial activity against several tested bacteria including , , and , but no growth inhibitory activity is observed against the other Gram-positive and Gram-negative bacteria. The selectivity index (Vero cell cytotoxicity/antimicrobial activity) of is approximately 17, and does not induce hemolysis even at a 100 μM concentration.