Fidaxomicin Inhibits Spore Production in Clostridium difficile
Fidaxomicin Inhibits Spore Production in Clostridium difficile
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DOI：
10.1093/cid/cis453
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发表时间：
2012-08-01
影响因子：
11.8
通讯作者：
Sonenshein, Abraham L.
中科院分区：
文献类型：
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作者：
Babakhani, Farah;Bouillaut, Laurent;Sonenshein, Abraham L.
非达霉素（Fidaxomicin， FDX）是一种新型窄谱抗菌药物，对艰难梭菌具有较强的杀菌活性。在最近的临床试验中，FDX在预防艰难梭菌感染复发方面优于万古霉素。减少复发的可能机制可能是通过抑制产孢作用。比较FDX及其主要代谢物OP-1118与万古霉素、甲硝唑和利福昔明对艰难梭菌生长和产孢动力学的影响。在细胞生长的早期固定阶段加入亚最低抑制浓度（sub- mic）的药物；然后在不同的时间间隔收集细胞，在含牛磺胆酸的培养基上定量总活细胞和耐热孢子数。采用定量逆转录酶聚合酶链反应比较2-2.5倍MIC下药物对艰难梭菌产孢基因表达的影响。当将FDX和OP-1118（1/4倍MIC）添加到艰难梭菌（包括流行的NAP1/BI/027菌株）的早期静止期细胞时，它们都能抑制产孢。相比之下，万古霉素、甲硝唑和利福昔明（在相似的亚mic）没有抑制孢子形成。比较药物处理后孢子数量增加到与无药物对照处理相同的水平。FDX和OP-1118也能抑制母细胞特异性（spoiid）和前孢子特异性（spoIIR）产孢基因的表达，但万古霉素的抑制作用不显著。FDX和OP-1118（与万古霉素、利福昔明和甲硝唑不同）都能有效抑制艰难梭菌的产孢。FDX对艰难梭菌产孢的抑制作用可能有助于其在维持临床反应和减少复发率方面的优异表现，也可能有利于减少该病原体的脱落和传播。
Fidaxomicin (FDX) is a novel antimicrobial agent with narrow-spectrum and potent bactericidal activity against Clostridium difficile. In recent clinical trials, FDX was superior to vancomycin in preventing recurrences of C. difficile infection. A possible mechanism of reducing recurrence may be through an inhibitory effect on sporulation. The effect of FDX and its major metabolite, OP-1118, on C. difficile growth and sporulation kinetics was compared with that of vancomycin, metronidazole, and rifaximin. Drugs at subminimum inhibitory concentrations (sub-MICs) were added to cells at an early stationary phase of growth; this was followed by collection of cells at various intervals for quantitation of total viable cell and heat-resistant spore counts on taurocholate-containing media. The effect of the drugs at 2-2.5x MIC on the expression of sporulation genes in C. difficile was also compared using quantitative reverse-transcriptase polymerase chain reaction. Both FDX and OP-1118 (1/4x MIC) inhibited sporulation when added to early-stationary-phase cells in C. difficile strains, including the epidemic NAP1/BI/027 strain. In contrast, vancomycin, metronidazole, and rifaximin (at similar sub-MICs) did not inhibit sporulation. The number of spores following treatment with comparator drugs increased to the same level as the no-drug control treatment. Expression of mother cell-specific (spoIIID) and forespore-specific (spoIIR) sporulation genes also was inhibited by FDX and OP-1118 but not significantly by vancomycin. Both FDX and OP-1118 (unlike vancomycin, rifaximin, and metronidazole) effectively inhibited sporulation by C. difficile. The inhibitory effect of FDX on C. difficile sporulation may contribute to its superior performance in sustaining clinical response and reducing recurrences and may also be beneficial in decreasing shedding and transmission of this pathogen.