Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Computing, University of Turku, Finland.
Enzymes. 2024;55:343-381. doi: 10.1016/bs.enz.2024.05.012. Epub 2024 Aug 6.
Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is still a major global health problem. According to the World Health Organization (WHO), TB still causes more deaths worldwide than any other infectious agent. Drug-sensitive TB is treatable using first-line drugs; treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB requires second- and third-line drugs. However, due to the long duration of treatment, the noncompliance of patients with different levels of resistance of Mtb to these drugs has worsened the situation. Previously developed anti-TB drugs targeted the replication machinery, protein synthesis, and cell wall biosynthesis pathways of Mtb. Therefore, novel drugs targeting alternate pathways crucial for the survival and pathogenesis of Mtb in the human host are needed. The genome of Mtb encodes three β-carbonic anhydrases (CAs) that are fundamental for pH homeostasis, hypoxia, survival, and pathogenesis. Recently, several studies have shown that the β-CAs of Mtb could be inhibited both in vitro and in vivo using small chemical molecules, suggesting that these enzymes could be novel targets for developing anti-TB compounds that are devoid of resistance by Mtb. In addition, homologs of β-CAs are absent in humans; therefore, drugs developed to target these enzymes might have minimal off-target effects. In this work, we describe the roles of β-CAs in Mtb and discuss bioinformatics and cheminformatics tools used in development and discovery of novel inhibitors of these enzymes. In addition, we summarize the in vitro and in vivo studies demonstrating that the β-CAs of Mtb are indeed druggable targets.
结核分枝杆菌（Mtb）可引起结核病（TB），仍然是一个重大的全球健康问题。根据世界卫生组织（WHO）的数据，TB 仍然是全球导致死亡人数最多的传染病病原体。使用一线药物可治疗药物敏感型 TB；治疗耐多药（MDR）和广泛耐药（XDR）TB 需要二线和三线药物。然而，由于治疗时间长，不同耐药程度的患者对这些药物的不依从性使情况恶化。以前开发的抗 TB 药物针对 Mtb 的复制机制、蛋白质合成和细胞壁生物合成途径。因此，需要针对 Mtb 在人体宿主中生存和发病机制至关重要的替代途径的新型药物。Mtb 的基因组编码三种β-碳酸酐酶（CA），这些酶对 pH 平衡、缺氧、生存和发病机制至关重要。最近，几项研究表明，使用小分子可在体外和体内抑制 Mtb 的β-CAs，这表明这些酶可能是开发抗 TB 化合物的新靶标，这些化合物不会被 Mtb 产生耐药性。此外，β-CAs 的同源物在人类中不存在；因此，针对这些酶开发的药物可能具有最小的脱靶效应。在这项工作中，我们描述了β-CAs 在 Mtb 中的作用，并讨论了用于开发和发现这些酶的新型抑制剂的生物信息学和化学信息学工具。此外，我们总结了体外和体内研究，证明 Mtb 的β-CAs 确实是可成药的靶标。
