Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, and The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Sci Rep. 2016 Sep 16;6:33642. doi: 10.1038/srep33642.
Prolonged use of broad-spectrum antibiotics disrupts the indigenous gut microbiota, which consequently enables toxigenic Clostridium difficile species to proliferate and cause infection. The burden of C. difficile infections was exacerbated with the outbreak of hypervirulent strains that produce copious amounts of enterotoxins and spores. In recent past, membrane-active agents have generated a surge of interest due to their bactericidal property with a low propensity for resistance. In this study, we capitalized on the antimicrobial property and low oral bioavailability of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. By broth microdilution techniques, we determined the MIC values of the anthelmintics against 16 C. difficile isolates of defined PCR-ribotype. The anthelmintics broadly inhibited C. difficile growth in vitro via a membrane depolarization mechanism. Interestingly, the salicylanilides were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. The salicylanilides were poorly active against select gut commensals (Bacteroides, Bifidobacterium and Lactobacillus species), and were non-hemolytic and non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their in vitro MICs and MBCs. The salicylanilide anthelmintics exhibit desirable properties for repositioning as anti-C. difficile agents.
长期使用广谱抗生素会破坏本土肠道微生物群，从而使产毒艰难梭菌得以增殖并引起感染。随着产毒能力更强的高毒力菌株的爆发，艰难梭菌感染的负担加剧了，这些菌株会产生大量的肠毒素和孢子。在最近，膜活性药物因其杀菌特性和低耐药倾向而引起了人们的极大兴趣。在这项研究中，我们利用驱虫药（氯硝柳胺、三氯苯达唑、硝氯酚、奥硝唑）的抗菌特性和低口服生物利用度来靶向肠道病原体。通过肉汤微量稀释技术，我们测定了驱虫药对 16 株确定的 PCR-核糖体分型艰难梭菌分离株的 MIC 值。驱虫药通过膜去极化机制广泛抑制艰难梭菌的体外生长。有趣的是，水杨酰苯胺类药物对 BI/NAP1/027 菌株 4118 的对数期和稳定期培养物具有杀菌作用。水杨酰苯胺类药物对肠道共生菌（拟杆菌属、双歧杆菌属和乳杆菌属）的活性较差，并且在其体外 MIC 和 MBC 范围内对 HepG2 和 HEK 293T/17 哺乳动物细胞系既非溶血也无毒。水杨酰苯胺类驱虫药具有作为抗艰难梭菌药物重新定位的理想特性。
