Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
School of Chemistry, University of Wollongong, NSW 2522, Australia.
Bioorg Med Chem Lett. 2014 Jan 15;24(2):595-600. doi: 10.1016/j.bmcl.2013.12.015. Epub 2013 Dec 10.
Current antibiotics for treating Clostridium difficile infections (CDI), that is, metronidazole, vancomycin and more recently fidaxomicin, are mostly effective but treatment failure and disease relapse remain as significant clinical problems. The shortcomings of these agents are attributed to their low selectivity for C. difficile over normal gut microflora and their ineffectiveness against C. difficile spores. This Letter reports that certain diarylacylhydrazones identified during a high-throughput screening/counter-screening campaign show selective activity against two Clostridium species (C. difficile and Clostridium perfringens) over common gut commensals. Representative examples are shown to possess activity similar to vancomycin against clinical C. difficile strains and to kill stationary-phase C. difficile cells, which are responsible for spore production. Structure-activity relationships with additional synthesised analogues suggested a protonophoric mechanism may play a role in the observed activity/selectivity and this was supported by the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) showing selective anti-Clostridium effects and activity similar to diarylacylhydrazones against stationary-phase C. difficile cells. Two diarylacylhydrazones were shown to be non-toxic towards human FaDu and Hep G2 cells indicating that further studies with the class are warranted towards new drugs for CDI.
目前用于治疗艰难梭菌感染（CDI）的抗生素，即甲硝唑、万古霉素和最近的非达霉素，大多是有效的，但治疗失败和疾病复发仍然是一个重大的临床问题。这些药物的缺点是它们对艰难梭菌的选择性低于正常肠道微生物群，并且对艰难梭菌孢子无效。这封信报告说，在高通量筛选/反向筛选活动中发现的某些二酰基酰肼对两种梭菌（艰难梭菌和产气荚膜梭菌）具有选择性活性，而对常见的肠道共生菌没有活性。代表性的例子显示出与万古霉素相似的活性，可抑制临床艰难梭菌菌株，并杀死导致孢子产生的静止期艰难梭菌细胞。与额外合成的类似物的构效关系表明质子载体机制可能在观察到的活性/选择性中起作用，这得到了众所周知的质子载体羰基氰化物 m-氯苯腙（CCCP）的支持，它显示出对艰难梭菌的选择性抗作用，并且对静止期艰难梭菌细胞的活性与二酰基酰肼相似。两种二酰基酰肼对人 FaDu 和 Hep G2 细胞均无毒性，表明需要对该类药物进行进一步研究，以开发用于 CDI 的新药。
