Cook Gregory M, Greening Chris, Hards Kiel, Berney Michael
Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
Department of Microbiology and Immunology, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand.
Adv Microb Physiol. 2014;65:1-62. doi: 10.1016/bs.ampbs.2014.08.001. Epub 2014 Nov 4.
The emergence and spread of drug-resistant pathogens and our inability to develop new antimicrobials to overcome resistance has inspired scientists to consider new targets for drug development. Cellular bioenergetics is an area showing promise for the development of new antimicrobials, particularly in the discovery of new anti-tuberculosis drugs where several new compounds have entered clinical trials. In this review, we have examined the bioenergetics of various bacterial pathogens, highlighting the versatility of electron donor and acceptor utilisation and the modularity of electron transport chain components in bacteria. In addition to re-examining classical concepts, we explore new literature that reveals the intricacies of pathogen energetics, for example, how Salmonella enterica and Campylobacter jejuni exploit host and microbiota to derive powerful electron donors and sinks; the strategies Mycobacterium tuberculosis and Pseudomonas aeruginosa use to persist in lung tissues; and the importance of sodium energetics and electron bifurcation in the chemiosmotic anaerobe Fusobacterium nucleatum. A combination of physiological, biochemical, and pharmacological data suggests that, in addition to the clinically-approved target F1Fo-ATP synthase, NADH dehydrogenase type II, succinate dehydrogenase, hydrogenase, cytochrome bd oxidase, and menaquinone biosynthesis pathways are particularly promising next-generation drug targets. The realisation of cellular energetics as a rich target space for the development of new antimicrobials will be dependent upon gaining increased understanding of the energetic processes utilised by pathogens in host environments and the ability to design bacterial-specific inhibitors of these processes.
耐药病原体的出现与传播，以及我们在开发新抗菌药物以克服耐药性方面的无能，促使科学家们去考虑药物开发的新靶点。细胞生物能量学是一个展现出开发新抗菌药物潜力的领域，特别是在新型抗结核药物的发现方面，已有几种新化合物进入了临床试验阶段。在本综述中，我们研究了各种细菌病原体的生物能量学，强调了细菌在电子供体和受体利用方面的多样性以及电子传递链组分的模块化。除了重新审视经典概念外，我们还探索了揭示病原体能量学复杂性的新文献，例如，肠炎沙门氏菌和空肠弯曲菌如何利用宿主和微生物群来获取强大的电子供体和电子阱；结核分枝杆菌和铜绿假单胞菌在肺组织中持续存在所采用的策略；以及钠能量学和电子分叉在化学渗透厌氧菌具核梭杆菌中的重要性。生理、生化和药理学数据的综合表明，除了临床批准的靶点F1Fo - ATP合酶外，II型NADH脱氢酶、琥珀酸脱氢酶、氢化酶、细胞色素bd氧化酶和甲萘醌生物合成途径是特别有前景的下一代药物靶点。要实现细胞能量学作为开发新抗菌药物的丰富靶点领域，将取决于对病原体在宿主环境中利用的能量过程有更多的了解，以及设计针对这些过程的细菌特异性抑制剂的能力。
