Bacteriology, Niigata Universitygrid.412181.fgrid.260975.f School of Medicine, Niigata, Japan.
Department of Biology, Natural and Computational Sciences Faculty, Assosa University, Assosa, Ethiopia.
Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0017122. doi: 10.1128/aac.00171-22. Epub 2022 Aug 15.
Tuberculosis remains a public health crisis and a health security threat. There is an urgent need to develop new antituberculosis drugs with novel modes of action to cure drug-resistant tuberculosis and shorten the chemotherapy period by sterilizing tissues infected with dormant bacteria. Lysocin E is an antibiotic that showed antibacterial activity against Staphylococcus aureus by binding to its menaquinone (commonly known as vitamin K). Unlike S. aureus, menaquinone is essential in both growing and dormant Mycobacterium tuberculosis. This study aims to evaluate the antituberculosis activities of lysocin E and decipher its mode of action. We show that lysocin E has high activity against both drug-susceptible and drug-resistant Mycobacterium tuberculosis var. tuberculosis and dormant mycobacteria. Lysocin E is likely bound to menaquinone, causing M. tuberculosis membrane disruption, inhibition of oxygen consumption, and ATP synthesis. Thus, we have concluded that the high antituberculosis activity of lysocin E is attributable to its synergistic effects of membrane disruption and respiratory inhibition. The efficacy of lysocin E against intracellular M. tuberculosis in macrophages was lower than its potent activity against M. tuberculosis in culture medium, probably due to its low ability to penetrate cells, but its efficacy in mice was still superior to that of streptomycin. Our findings indicate that lysocin E is a promising lead compound for the development of a new tuberculosis drug that cures drug-resistant and latent tuberculosis in a shorter period.
结核病仍然是一个公共卫生危机和健康安全威胁。迫切需要开发具有新作用模式的新型抗结核药物，以治愈耐药结核病并通过杀菌组织中休眠细菌来缩短化疗期。Lysin E 是一种抗生素，通过与金黄色葡萄球菌的menaquinone（通常称为维生素 K）结合来显示对金黄色葡萄球菌的抗菌活性。与金黄色葡萄球菌不同，menaquinone在生长和休眠的结核分枝杆菌中都是必需的。本研究旨在评估 lysocin E 的抗结核活性并破译其作用机制。我们表明 lysocin E 对耐多药和耐药结核分枝杆菌 var. 均具有高活性。结核分枝杆菌和休眠分枝杆菌。Lysin E 可能与 menaquinone 结合，导致结核分枝杆菌膜破裂、氧消耗抑制和 ATP 合成抑制。因此，我们得出结论，lysocin E 的高抗结核活性归因于其膜破坏和呼吸抑制的协同作用。Lysin E 对巨噬细胞中胞内结核分枝杆菌的疗效低于其对培养基中结核分枝杆菌的有效活性，可能是由于其穿透细胞的能力较低，但在小鼠中的疗效仍优于链霉素。我们的研究结果表明，lysocin E 是一种有前途的先导化合物，可用于开发一种新的结核病药物，以在更短的时间内治愈耐药和潜伏性结核病。
