Kuang Wenbin, Zhang Haolin, Wang Xiao, Yang Peng
State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharm Sin B. 2022 Aug;12(8):3201-3214. doi: 10.1016/j.apsb.2022.04.014. Epub 2022 Apr 27.
(MTB) utilizes multiple mechanisms to obtain antibiotic resistance during the treatment of infections. In addition, the biofilms, secreted by MTB, can further protect the latter from the contact with drug molecules and immune cells. These self-defending mechanisms lay a formidable challenge to develop effective therapeutic agents against chronic and recurring antibiotic-tolerant MTB infections. Although several inexpensive and effective drugs (isoniazid, rifampicin, pyrazinamide and ethambutol) have been discovered for the treatment regimen, MTB continues to cause considerable morbidity and mortality worldwide. Antibiotic resistance and tolerance remain major global issues, and innovative therapeutic strategies are urgently needed to address the challenges associated with pathogenic bacteria. Gratifyingly, the cell wall synthesis of tubercle bacilli requires the participation of many enzymes which exclusively exist in prokaryotic organisms. These enzymes, absent in human hepatocytes, are recognized as promising targets to develop anti-tuberculosis drug. In this paper, we discussed the critical roles of potential drug targets in regulating cell wall synthesis of MTB. And also, we systematically reviewed the advanced development of novel bioactive compounds or drug leads for inhibition of cell wall synthesis, including their discovery, chemical modification, and evaluation.
结核分枝杆菌（MTB）在感染治疗过程中利用多种机制获得抗生素耐药性。此外，MTB分泌的生物膜可进一步保护其免受药物分子和免疫细胞的接触。这些自我防御机制对开发针对慢性和复发性耐抗生素MTB感染的有效治疗药物构成了巨大挑战。尽管已发现几种廉价且有效的药物（异烟肼、利福平、吡嗪酰胺和乙胺丁醇）用于治疗方案，但MTB在全球范围内仍导致相当高的发病率和死亡率。抗生素耐药性和耐受性仍然是主要的全球问题，迫切需要创新的治疗策略来应对与病原菌相关的挑战。令人欣慰的是，结核杆菌的细胞壁合成需要许多仅存在于原核生物中的酶参与。这些在人类肝细胞中不存在的酶被认为是开发抗结核药物的有希望的靶点。在本文中，我们讨论了潜在药物靶点在调节MTB细胞壁合成中的关键作用。此外，我们系统地综述了用于抑制细胞壁合成的新型生物活性化合物或药物先导物的前沿进展，包括它们的发现、化学修饰和评估。
