Microbiotix, Inc., Worcester, Massachusetts, USA.
Antimicrob Agents Chemother. 2012 Sep;56(9):4786-92. doi: 10.1128/AAC.00508-12. Epub 2012 Jun 25.
Clostridium difficile infection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, the in vitro and in vivo efficacies of MBX-500 were explored against the Gram-positive anaerobe, C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.
艰难梭菌感染（CDI）可引起中度至重度疾病，导致腹泻和伪膜性结肠炎。由于产生炎症诱导毒素、耐药性发展和高复发率，CDI 难以治疗。只有两种抗生素被批准用于治疗 CDI，而治疗药物的管道中几乎没有新的药物。MBX-500 是一种混合抗菌药物，由与氟喹诺酮 DNA 螺旋酶/拓扑异构酶抑制剂相连的苯胺尿嘧啶 DNA 聚合酶抑制剂组成，具有作为治疗 CDI 的新疗法的潜力。由于 MBX-500 抑制三个细菌靶标，因此以前显示出对耐药性发展的最小敏感性。在本研究中，研究了 MBX-500 对革兰氏阳性厌氧菌艰难梭菌的体外和体内疗效。MBX-500 对近 50 个分离株表现出效力，包括氟喹诺酮耐药、毒素过度产生 NAP1/027 核糖体型，其效力与比较抗生素万古霉素和甲硝唑相当。此外，MBX-500 是一种窄谱药物，对许多其他肠道厌氧菌活性差。MBX-500 在艰难梭菌的产毒仓鼠模型的急性和复发性感染中具有活性，在急性感染中表现出完全保护作用，并使 70%的动物预防复发。用 MBX-500 治疗的仓鼠体重增加明显大于用万古霉素治疗的仓鼠。最后，MBX-500 在 CDI 的小鼠模型中有效，再次显示出完全保护作用，并使受治疗动物的体重几乎正常增加。这些针对 CDI 的选择性特征支持进一步开发 MBX-500 用于治疗 CDI。
