Tasneen Rokeya, Williams Kathy, Amoabeng Opokua, Minkowski Austin, Mdluli Khisimuzi E, Upton Anna M, Nuermberger Eric L
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Global Alliance for TB Drug Development, New York, New York, USA.
Antimicrob Agents Chemother. 2015 Jan;59(1):129-35. doi: 10.1128/AAC.03822-14. Epub 2014 Oct 20.
New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.
为了缩短或简化对药物敏感和耐药形式结核病的治疗，人们正在探索基于两种或更多新型药物的新方案。PA-824是一种硝基咪唑并恶嗪，目前正处于II期试验阶段，已显示出单独使用以及与新批准的药物贝达喹啉联合使用，或与吡嗪酰胺联合使用（无论是否联用莫西沙星）时具有显著的早期杀菌活性。在PA-824继续研发的同时，已发现一种潜在的下一代衍生物TBA-354在体外的效力优于PA-824，并且在代谢稳定性方面比正在临床开发的另一种硝基咪唑衍生物地拉曼德更高。在本研究中，我们比较了PA-824和TBA-354在小鼠模型治疗初始强化期和持续期作为单一疗法的活性，以及与贝达喹啉加吡嗪酰胺、舒替利啶和/或氯法齐明联合使用时的活性。单一疗法研究表明，TBA-354的效力比PA-824高5至10倍，但某些突变体对PA-824和地拉曼德具有交叉耐药性。联合疗法研究表明，TBA-354与贝达喹啉联合使用时的效力比PA-824高2至4倍，并且当以与PA-824相当的剂量给药时，TBA-354显示出更好的杀菌效果。也许最重要的是，添加任何一种硝基咪唑都能显著提高贝达喹啉和舒替利啶（无论是否联用吡嗪酰胺）的杀菌活性，证实了每种药物在这种可能具有普遍活性的短程治疗方案中的价值。
