Black Todd A, Buchwald Ulrike K
Global Alliance for TB Drug Development, 40 Wall Street, 24th Floor, New York, NY 10005, USA.
J Clin Tuberc Other Mycobact Dis. 2021 Nov 5;25:100285. doi: 10.1016/j.jctube.2021.100285. eCollection 2021 Dec.
The clinical development and regulatory approval of bedaquiline, delamanid and pretomanid over the last decade brought about significant progress in the management of drug-resistant tuberculosis, providing all-oral regimens with favorable safety profiles. The Nix-TB and ZeNix trials of a bedaquiline - pretomanid - linezolid regimen demonstrated for the first time that certain forms of drug-resistant tuberculosis can be cured in the majority of patients within 6 months. Ongoing Phase 3 studies containing these drugs may further advance optimized regimen compositions. Investigational drugs in clinical development that target clinically validated mechanisms, such as second generation oxazolidinones (sutezolid, delpazolid, TBI-223) and diarylquinolines (TBAJ-876 and TBAJ-587) promise improved potency and/or safety compared to the first-in-class drugs. Compounds with novel targets involved in diverse bacterial functions such as cell wall synthesis (DrpE1, MmpL3), electron transport, DNA synthesis (GyrB), cholesterol metabolism and transcriptional regulation of ethionamide bioactivation pathways have advanced to early clinical studies with the potential to enhance antibacterial activity when added to new or established anti-TB drug regimens. Clinical validation of preclinical and animal model predictions of new anti-TB regimens may further improve the translational value of these models to identify optimal anti-TB therapies.
过去十年中，贝达喹啉、德拉马尼和普瑞玛尼的临床开发及监管批准在耐多药结核病的管理方面取得了重大进展，提供了安全性良好的全口服治疗方案。贝达喹啉-普瑞玛尼-利奈唑胺方案的Nix-TB和ZeNix试验首次证明，某些形式的耐多药结核病在大多数患者中可在6个月内治愈。正在进行的包含这些药物的3期研究可能会进一步推进优化治疗方案的组成。临床开发中的研究性药物针对临床验证的机制，如第二代恶唑烷酮类（舒替唑胺、地帕唑胺、TBI-223）和二芳基喹啉类（TBAJ-876和TBAJ-587），与同类首创药物相比，有望提高效力和/或安全性。具有参与多种细菌功能的新靶点的化合物，如细胞壁合成（DrpE1、MmpL3）、电子传递、DNA合成（GyrB）、胆固醇代谢以及乙硫异烟胺生物激活途径的转录调控，已进入早期临床研究，当添加到新的或已确立的抗结核药物方案中时，有可能增强抗菌活性。对新抗结核方案的临床前和动物模型预测进行临床验证，可能会进一步提高这些模型的转化价值，以确定最佳抗结核治疗方法。
