School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia.
PeerJ. 2024 Nov 14;12:e18404. doi: 10.7717/peerj.18404. eCollection 2024.
Tuberculosis (TB) caused by has been a threat to human health for thousands of years and still leads to millions of deaths each year. TB is a disease that is refractory to treatment, partially due to its capacity for in-host persistence. The cell wall of mycobacteria, rich in mycolic acid, is broadly associated with bacterial persistence together with antimicrobial and immunological resistance. Enzymes for the biosynthesis of bacterial peptidoglycan, an essential component of the cell wall, have been addressed and considered as appealing drug targets in pathogens. Significant effort has been dedicated to finding inhibitors that hinder peptidoglycan biosynthesis, many with demonstrated enzymatic inhibition being published. One family of critical biosynthetic enzymes are the Mur enzymes, with many enzyme specific inhibitors having been reported. However, a lesser developed strategy which may have positive clinical implications is to take advantage of the common structural and catalytic characteristics among Mur enzymes and to allow simultaneous, multiple Mur inhibition, and avert the development of drug resistance. relies on these essential Mur enzymes, with the best-known subset being Mur ligases, but also utilizes unique functions of atypical transpeptidases resulting in peptidoglycan peptide cross-linking beneficial to the bacteria's capacity for chronic persistence in humans. A systematic review is now needed, with an emphasis on . The urgent development of novel anti-TB agents to counter rapidly developing drug resistance requires a revisit of the literature, past successes and failures, in an attempt to reveal liabilities in critical cellular functions and drive innovation.
结核分枝杆菌引起的结核病已经威胁人类健康数千年，每年仍导致数百万人死亡。结核病是一种难治性疾病，部分原因是其在宿主体内的持续存在能力。分枝杆菌的细胞壁富含分枝菌酸，与细菌的持续存在以及抗微生物和免疫抗性广泛相关。细菌肽聚糖生物合成的酶是细胞壁的重要组成部分，已被确定为病原体中具有吸引力的药物靶点。已经做出了巨大的努力来寻找阻碍肽聚糖生物合成的抑制剂，其中许多已被证明具有酶抑制作用。一类关键的生物合成酶是 Mur 酶，已经报道了许多针对特定酶的抑制剂。然而，一种不太发达的策略可能具有积极的临床意义，即利用 Mur 酶之间的共同结构和催化特性，允许同时进行多种 Mur 抑制，从而避免耐药性的发展。 依赖于这些必需的 Mur 酶，其中最著名的亚组是 Mur 连接酶，但也利用了非典型转肽酶的独特功能，导致肽聚糖肽交联，有利于细菌在人类中长期持续存在的能力。现在需要进行系统评价，重点是 。为了应对迅速发展的耐药性，迫切需要开发新型抗结核药物，这需要重新审视文献、过去的成功和失败，试图揭示关键细胞功能中的缺陷，并推动创新。
