Stolz Brice J, Abouelkhair Ahmed A, Seleem Mohamed N
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America.
PLoS One. 2024 Dec 13;19(12):e0309624. doi: 10.1371/journal.pone.0309624. eCollection 2024.
Clostridioides difficile is a major cause of nosocomial infections, often associated with individuals who have gut dysbiosis from previous antibiotic therapies. C. difficile infections (CDI) have a high recurrence rate and impose significant financial and mortality burdens on the healthcare system. Therefore, novel anti-C. difficile drugs are urgently needed to treat and reduce the severity and recurrence of infection. In this study, we screened a library of 618 antiviral drugs to identify a potential candidate for repurposing as novel anti-C. difficile therapeutics. Following our preliminary screening, we identified 9 novel compounds that inhibited C. difficile at a concentration of 16 μM or lower. Among these, 4 antiviral compounds demonstrated the most potent anti-C. difficile activity against a panel of 15 C. difficile isolates, with minimum inhibitory concentrations (MICs) comparable to the drug of choice, vancomycin. These include rottlerin (MIC50 = 0.25 μg/mL), α-mangostin (MIC50 = 1 μg/mL), dryocrassin ABBA (MIC50 = 1 μg/mL), and obefazimod (MIC50 = 4 μg/mL). All exhibited minimal to no activity against representative members of the human gut microbiota. Interestingly, α-mangostin, a natural xanthone derived from the mangosteen fruit, exhibited strong bactericidal action, clearing a high inoculum of C. difficile in less than an hour. All other drugs exhibited bacteriostatic activity. Given their characteristics, these compounds show great promise as novel treatments for CDI.
艰难梭菌是医院感染的主要原因，通常与先前接受抗生素治疗导致肠道菌群失调的个体有关。艰难梭菌感染（CDI）复发率高，给医疗系统带来了巨大的经济负担和死亡负担。因此，迫切需要新型抗艰难梭菌药物来治疗并降低感染的严重程度和复发率。在本研究中，我们筛选了一个包含618种抗病毒药物的文库，以确定一种有潜力重新用作新型抗艰难梭菌治疗药物的候选药物。经过初步筛选，我们鉴定出9种新型化合物，它们在浓度为16 μM或更低时可抑制艰难梭菌。其中，4种抗病毒化合物对一组15株艰难梭菌分离株表现出最有效的抗艰难梭菌活性，其最低抑菌浓度（MIC）与首选药物万古霉素相当。这些化合物包括洛替林（MIC50 = 0.25 μg/mL）、α-山竹黄酮（MIC50 = 1 μg/mL）、绵马贯众素ABBA（MIC50 = 1 μg/mL）和奥贝胆酸（MIC50 = 4 μg/mL）。所有这些化合物对人类肠道微生物群的代表性成员表现出最小活性或无活性。有趣的是，α-山竹黄酮是一种从山竹果实中提取的天然氧杂蒽酮，表现出强大的杀菌作用，能在不到一小时内清除高接种量的艰难梭菌。所有其他药物均表现出抑菌活性。鉴于它们的特性，这些化合物作为CDI的新型治疗方法具有很大的前景。
