Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt.
J Antibiot (Tokyo). 2020 Jun;73(6):392-409. doi: 10.1038/s41429-020-0288-3. Epub 2020 Mar 4.
Clostridium difficile is a leading cause of morbidity and mortality particularly in hospital settings. In addition, treatment is very challenging due to the scarcity of effective therapeutic options. Thus, there remains an unmet need to identify new therapeutic agents capable of treating C. difficile infections. In the current study, we screened two FDA-approved drug libraries against C. difficile. Out of almost 3200 drugs screened, 50 drugs were capable of inhibiting the growth of C. difficile. Remarkably, some of the potent inhibitors have never been reported before and showed activity in a clinically achievable range. Structure-activity relationship analysis of the active hits clustered the potent inhibitors into four chemical groups; nitroimidazoles (MIC = 0.06-2.7 μM), salicylanilides (MIC = 0.2-0.6 μM), imidazole antifungals (MIC = 4.8-11.6 μM), and miscellaneous group (MIC = 0.4-22.2 μM). The most potent drugs from the initial screening were further evaluated against additional clinically relevant strains of C. difficile. Moreover, we tested the activity of potent inhibitors against representative strains of human normal gut microbiota to investigate the selectivity of the inhibitors towards C. difficile. Overall, this study provides a platform that could be used for further development of potent and selective anticlostridial antibiotics.
艰难梭菌是发病率和死亡率的主要原因，特别是在医院环境中。此外，由于有效的治疗选择有限，治疗极具挑战性。因此，仍然需要确定能够治疗艰难梭菌感染的新治疗剂。在目前的研究中，我们筛选了两种 FDA 批准的药物库来对抗艰难梭菌。在筛选的近 3200 种药物中，有 50 种药物能够抑制艰难梭菌的生长。值得注意的是，一些强效抑制剂以前从未报道过，并且在临床可达到的范围内具有活性。活性命中物的构效关系分析将强效抑制剂分为四个化学基团；硝基咪唑类（MIC=0.06-2.7μM）、水杨酰苯胺类（MIC=0.2-0.6μM）、咪唑类抗真菌药（MIC=4.8-11.6μM）和杂项组（MIC=0.4-22.2μM）。最初筛选出的最有效药物进一步针对其他临床相关的艰难梭菌菌株进行了评估。此外，我们测试了强效抑制剂对代表人类正常肠道微生物群的菌株的活性，以研究抑制剂对艰难梭菌的选择性。总的来说，这项研究提供了一个平台，可用于进一步开发强效和选择性的抗梭菌抗生素。
