Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA.
Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, 47907, USA.
Sci Rep. 2020 Apr 6;10(1):5966. doi: 10.1038/s41598-020-63029-0.
Clostridioides difficile is the most common cause of healthcare-associated diarrhea. Infection of the gastrointestinal tract with this Gram-positive, obligate anaerobe can lead to potentially life-threatening conditions in the antibiotic-treated populace. New therapeutics are urgently needed to treat this infection and prevent its recurrence. Here, we screened two libraries from the National Cancer Institute, namely, the natural product set III library (117 compounds) and the approved oncology drugs set V library (114 compounds), against C. difficile. In the two libraries screened, 17 compounds from the natural product set III library and 7 compounds from the approved oncology drugs set V library were found to exhibit anticlostridial activity. The most potent FDA-approved drugs (mitomycin C and mithramycin A) and a promising natural product (aureomycin) were further screened against 20 clinical isolates of C. difficile. The anticancer drugs, mitomycin C (MIC = 0.25 μg/ml) and mithramycin A (MIC = 0.015 μg/ml), and the naturally derived tetracycline derivative, aureomycin (MIC = 0.06 μg/ml), exhibited potent activity against C. difficile strains. Mithramycin A and aureomycin were further found to inhibit toxin production by this pathogen. Given their efficacy, these compounds can provide a quick supplement to current treatment to address the unmet needs in treating C. difficile infection and preventing its recurrence.
艰难梭菌是最常见的医源性腹泻病原体。这种革兰阳性、专性厌氧菌感染胃肠道，可能导致接受抗生素治疗的人群出现危及生命的情况。迫切需要新的疗法来治疗这种感染并预防其复发。在这里，我们针对艰难梭菌筛选了两个来自美国国立癌症研究所的文库，即天然产物集 III 文库（117 种化合物）和已批准的肿瘤药物集 V 文库（114 种化合物）。在所筛选的两个文库中，天然产物集 III 文库中有 17 种化合物和已批准的肿瘤药物集 V 文库中有 7 种化合物显示出抗艰难梭菌活性。进一步针对 20 株临床分离的艰难梭菌筛选了最有效的 FDA 批准药物（丝裂霉素 C 和米托霉素 A）和一种有前途的天然产物（金霉素）。抗癌药物丝裂霉素 C（MIC=0.25μg/ml）和米托霉素 A（MIC=0.015μg/ml）以及天然衍生的四环素衍生物金霉素（MIC=0.06μg/ml）对艰难梭菌菌株表现出很强的活性。进一步发现米托霉素 A 和金霉素抑制了该病原体的毒素产生。鉴于它们的疗效，这些化合物可以为当前的治疗方法提供快速补充，以满足治疗艰难梭菌感染和预防其复发的未满足需求。
