Manjunatha Ujjini, Boshoff Helena Im, Barry Clifton E
Novartis Institute for Tropical Diseases; Singapore, Singapore.
Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926.
The bicyclic nitroimidazole PA-824 is a pro-drug with a very complex mechanism of action active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. Microarray analysis of the mode of action of PA-824 showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism. However, the structure-activity relationships governing aerobic activity do not parallel the relationships determining anaerobic activity. Based on the metabolite profiling of PA-824 and various derivatives by Ddn-mediated activation, we have shown that PA-824 acts directly as an NO donor.1 This respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by PA-824. The effect of PA-824 on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment. Thus, transcriptional profiling provided valuable clues to elucidating the molecular mechanism of mycobacterial killing.
双环硝基咪唑PA - 824是一种前体药物，其作用机制非常复杂，对正在复制的以及缺氧、非复制状态的结核分枝杆菌均有活性。对PA - 824作用模式的微阵列分析显示，它对细胞壁抑制（如异烟肼）和呼吸中毒（如氰化物）相关基因均有令人困惑的混合效应。该药物的需氧杀菌机制似乎涉及通过一种尚未明确的分子机制抑制细胞壁分枝菌酸的生物合成。然而，决定需氧活性的构效关系与决定厌氧活性的关系并不平行。基于Ddn介导的激活作用对PA - 824及其各种衍生物进行代谢物谱分析，我们发现PA - 824可直接作为一氧化氮供体。通过释放一氧化氮导致的这种呼吸中毒似乎是PA - 824厌氧活性的关键因素。在缺氧非复制条件下，PA - 824对呼吸复合体的影响也表现为细胞内ATP水平迅速下降，这同样类似于氰化物处理时观察到的情况。因此，转录谱分析为阐明分枝杆菌杀伤的分子机制提供了有价值的线索。
