Division of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, Odisha, India; Post-Graduate Department of Biotechnology, Utkal University, Bhubaneswar 751004, Odisha, India.
Division of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, Odisha, India.
Int J Biol Macromol. 2023 Dec 31;253(Pt 2):126771. doi: 10.1016/j.ijbiomac.2023.126771. Epub 2023 Sep 6.
Antibiotics form our frontline therapy against disease-causing bacteria. Unfortunately, antibiotic resistance is becoming more common, threatening a future where these medications can no longer cure infections. Furthermore, the emergence of multidrug-resistant (MDR), totally drug-resistant (TDR), and extensively drug-resistant (XDR) tuberculosis has increased the urgency of discovering new therapeutic leads with unique modes of action. Some natural peptides derived from actinomycetes, such as Cyclomarin A, Lassomycin, Rufomycin I, and Ecumicin, have potent and specific bactericidal activity against Mycobacterium tuberculosis, with the specificity owing to the fact that these peptides target the ClpC1 ATPase, an essential enzyme in mycobacteria, and inhibit/activate the proteolytic activity of the ClpC1/P1/P2 complex that participates in protein homeostasis. Here, we report the high-resolution crystal structure of the N-terminal domain of ClpC1 (ClpC1 NTD) in complex with Lassomycin, showing the specific binding mode of Lassomycin. In addition, the work also compares the Lassomycin complex structure with the previously known structures of ClpC1 NTD in complex with other natural peptides such as Cyclomarin A, Rufomycin I, and Ecumicin.
抗生素是我们对抗致病细菌的一线治疗药物。不幸的是，抗生素耐药性变得越来越普遍，威胁着这些药物将不再能够治愈感染的未来。此外，耐多药（MDR）、完全耐药（TDR）和广泛耐药（XDR）结核分枝杆菌的出现增加了发现具有独特作用模式的新治疗方法的紧迫性。一些来源于放线菌的天然肽，如环马菌素 A、拉索霉素、鲁福霉素 I 和埃库霉素，对结核分枝杆菌具有强大而特异的杀菌活性，其特异性归因于这些肽靶向 ClpC1 ATP 酶，这是分枝杆菌中的一种必需酶，并抑制/激活参与蛋白质平衡的 ClpC1/P1/P2 复合物的蛋白水解活性。在这里，我们报告了 ClpC1 的 N 端结构域（ClpC1 NTD）与拉索霉素复合物的高分辨率晶体结构，显示了拉索霉素的特异性结合模式。此外，这项工作还比较了拉索霉素复合物结构与之前已知的 ClpC1 NTD 与其他天然肽（如环马菌素 A、鲁福霉素 I 和埃库霉素）复合物的结构。
