Department of Molecular Genetics and Microbiology, Stony Brook University, 11794, Stony Brook, NY, USA.
Department of Pharmacological Sciences, Stony Brook University, 11794, Stony Brook, NY, USA.
Curr Top Microbiol Immunol. 2019;420:49-72. doi: 10.1007/82_2018_125.
Mycobacteria, from saprophytic to pathogenic species, encounter diverse environments that demand metabolic versatility and rapid adaptation from these bacteria for their survival. The human pathogen Mycobacterium tuberculosis, for example, can enter a reversible state of dormancy in which it is metabolically active, but does not increase in number, and which is believed to enable its survival in the human host for years, with attendant risk for reactivation to active tuberculosis. Driven by the need to combat mycobacterial diseases like tuberculosis, efforts to understand such adaptations have benefitted in recent years from application of activity-based probes. These studies have been inspired by the potential of these chemical tools to uncover protein function for previously unannotated proteins, track shifts in protein activity as a function of environment, and provide a streamlined method for screening and developing inhibitors. Here we seek to contextualize progress thus far with achieving these goals and highlight the unique challenges and opportunities for activity-based probes to further our understanding of protein function and regulation, bacterial physiology, and antibiotic development.
分枝杆菌，从腐生到致病物种，遇到了多样化的环境，这些环境要求这些细菌具有代谢多功能性和快速适应性才能生存。例如，人类病原体结核分枝杆菌可以进入一种可逆的休眠状态，在这种状态下，它的新陈代谢是活跃的，但数量不会增加，人们认为这种状态使它能够在人类宿主中存活数年，同时也存在重新激活为活动性肺结核的风险。为了对抗结核病等分枝杆菌病，人们迫切需要了解这些适应机制，近年来，基于活性的探针的应用为此提供了帮助。这些研究的灵感来自于这些化学工具的潜力，它们可以揭示以前未注释的蛋白质的功能，跟踪蛋白质活性随环境变化的情况，并为筛选和开发抑制剂提供一种简化的方法。在这里，我们试图结合迄今为止在实现这些目标方面的进展，强调基于活性的探针在进一步了解蛋白质功能和调节、细菌生理学和抗生素开发方面的独特挑战和机遇。
