Novel FR-900493 Analogues That Inhibit the Outgrowth of <i>Clostridium difficile</i> Spores

Abstract

The spectrum of antibacterial activity for the nucleoside antibiotic FR-900493 (<b>1</b>) can be extended by chemical modifications. We have generated a small focused library based on the structure of <b>1</b> and identified UT-17415 (<b>9</b>), UT-17455 (<b>10</b>), UT-17460 (<b>11</b>), and UT-17465 (<b>12</b>), which exhibit anti-<i>Clostridium difficile</i> growth inhibitory activity. These analogues also inhibit the outgrowth of <i>C. difficile</i> spores at 2× minimum inhibitory concentration. One of these analogues, <b>11</b>, relative to <b>1</b> 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 <b>11</b> displays antimicrobial activity against several tested bacteria including <i>Bacillus subtilis</i>, <i>Clostridium spp.</i>, and <i>Mycobacterium smegmatis</i>, but no growth inhibitory activity is observed against the other Gram-positive and Gram-negative bacteria. The selectivity index (Vero cell cytotoxicity/<i>C. difficile</i>antimicrobial activity) of <b>11</b> is approximately 17, and <b>11</b> does not induce hemolysis even at a 100 μM concentration.