Mitachi Katsuhiko, Yun Hyun Gi, Kurosu Sara M, Eslamimehr Shakiba, Lemieux Maddie R, Klaić Lada, Clemons William M, Kurosu Michio
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, Tennessee 38163, United States.
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E. California Blvd, Pasadena, California 91125, United States.
ACS Omega. 2018 Feb 28;3(2):1726-1739. doi: 10.1021/acsomega.7b01740. Epub 2018 Feb 9.
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.
核苷类抗生素FR-900493（）的抗菌活性谱可通过化学修饰得到扩展。我们基于的结构构建了一个小型聚焦文库，并鉴定出UT-17415（）、UT-17455（）、UT-17460（）和UT-17465（），它们具有抗生长抑制活性。这些类似物在2倍最小抑菌浓度下也能抑制孢子的生长。其中一种类似物，相对于，对磷酸化MurNAc-五肽转位酶（MraY）和聚异戊二烯磷酸-GlcNAc-1-磷酸转移酶（WecA）的活性分别高出180倍和15倍。磷酸转移酶抑制剂对包括、和在内的几种受试细菌具有抗菌活性，但对其他革兰氏阳性和革兰氏阴性细菌未观察到生长抑制活性。的选择性指数（Vero细胞毒性/抗菌活性）约为17，即使在100μM浓度下也不会诱导溶血。
