PDF(Pubmed)
Abstract：
Bacillus anthracis is a Gram-positive Centers for Disease Control and Prevention category \"A\" biothreat pathogen. Without early treatment, inhalation of anthrax spores with progression to inhalational anthrax disease is associated with high fatality rates. Gepotidacin is a novel first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is being evaluated for use against biothreat and conventional pathogens. Gepotidacin selectively inhibits bacterial DNA replication via a unique binding mode and has in vitro activity against a collection of B. anthracis isolates including antibacterial-resistant strains, with the MIC90 ranging from 0.5 to 1 µg/mL. In vivo activity of gepotidacin was also evaluated in the New Zealand White rabbit model of inhalational anthrax. The primary endpoint was survival, with survival duration and bacterial clearance as secondary endpoints. The trigger for treatment was the presence of anthrax protective antigen in serum. New Zealand White rabbits were dosed intravenously for 5 days with saline or gepotidacin at 114 mg/kg/d to simulate a dosing regimen of 1,000 mg intravenous (i.v.) three times a day (TID) in humans. Gepotidacin provided a survival benefit compared to saline control, with 91% survival (P-value: 0.0001). All control animals succumbed to anthrax and were found to be blood- and organ culture-positive for B. anthracis. The novel mode of action, in vitro microbiology, preclinical safety, and animal model efficacy data, which were generated in line with Food and Drug Administration Animal Rule, support gepotidacin as a potential treatment for anthrax in an emergency biothreat situation.
摘要：
炭疽芽孢杆菌是革兰氏阳性疾病控制和预防中心类别“A”生物病原体。如果没有早期治疗，吸入炭疽孢子并进展为吸入性炭疽疾病与高死亡率相关。Gepotidacin是一种新型的三氮杂萘并环亚抗生素，可通过独特的作用机制抑制细菌DNA的复制，并正在评估其针对生物细菌和常规病原体的用途。Gepotidacin通过独特的结合模式选择性地抑制细菌DNA复制，并具有抗炭疽杆菌分离株（包括抗细菌菌株）的体外活性，MIC90的范围为0.5至1µg/mL。还在新西兰白兔吸入性炭疽模型中评估了gapotidacin的体内活性。主要终点是生存，以存活时间和细菌清除为次要终点。治疗的触发因素是血清中存在炭疽保护性抗原。将新西兰白兔以114mg/kg/d的盐水或吉普他星静脉内给药5天，以模拟人每天三次（TID）的1,000mg静脉内（i.v.）给药方案。与盐水对照相比，吉泊地星提供了生存益处，生存率为91%（P值：0.0001）。所有对照动物都死于炭疽，并被发现对炭疽杆菌呈血液和器官培养阳性。新颖的行动模式，体外微生物学，临床前安全性,和动物模型功效数据，它们是根据食品和药物管理局动物规则生成的，支持gepotidacin在紧急生物威胁情况下作为炭疽的潜在治疗方法。
