SAMRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical TB Research, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
Current address: Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, University of Stellenbosch, South Africa.
Microbiol Spectr. 2019 Jul;7(4). doi: 10.1128/microbiolspec.GPP3-0067-2019.
is the cause of tuberculosis (TB), a disease which continues to overwhelm health systems in endemic regions despite the existence of effective combination chemotherapy and the widespread use of a neonatal anti-TB vaccine. For a professional pathogen, retains a surprisingly large proportion of the metabolic repertoire found in nonpathogenic mycobacteria with very different lifestyles. Moreover, evidence that additional functions were acquired during the early evolution of the complex suggests the organism has adapted (and augmented) the metabolic pathways of its environmental ancestor to persistence and propagation within its obligate human host. A better understanding of pathogenicity, however, requires the elucidation of metabolic functions under disease-relevant conditions, a challenge complicated by limited knowledge of the microenvironments occupied and nutrients accessed by bacilli during host infection, as well as the reliance in experimental mycobacteriology on a restricted number of experimental models with variable relevance to clinical disease. Here, we consider metabolism within the framework of an intimate host-pathogen coevolution. Focusing on recent advances in our understanding of mycobacterial metabolic function, we highlight unusual adaptations or departures from the better-characterized model intracellular pathogens. We also discuss the impact of these mycobacterial "innovations" on the susceptibility of to existing and experimental anti-TB drugs, as well as strategies for targeting metabolic pathways. Finally, we offer some perspectives on the key gaps in the current knowledge of fundamental mycobacterial metabolism and the lessons which might be learned from other systems.
是结核病（TB）的病原体，尽管存在有效的联合化疗和广泛使用新生儿抗结核疫苗，但在流行地区，这种疾病仍然使卫生系统不堪重负。对于一种专业病原体来说，它保留了大量在生活方式非常不同的非致病性分枝杆菌中发现的代谢产物。此外，有证据表明，在 复合体的早期进化过程中获得了额外的功能，这表明该生物体已经适应（并增强）了其环境祖先的代谢途径，以在其专性人类宿主中持续存在和繁殖。然而，要更好地了解其致病性，就需要在与疾病相关的条件下阐明其代谢功能，这一挑战因对杆菌在宿主感染期间占据的微环境和获得的营养物质的了解有限，以及实验分枝杆菌学中对少数实验模型的依赖而变得复杂，这些模型与临床疾病的相关性各不相同。在这里，我们根据密切的宿主-病原体共同进化框架来考虑 的代谢。我们重点介绍了最近在理解分枝杆菌代谢功能方面的进展，强调了分枝杆菌与更好地研究的细胞内病原体不同的特殊适应或偏离。我们还讨论了这些分枝杆菌的“创新”对现有和实验性抗结核药物的敏感性的影响，以及针对代谢途径的策略。最后，我们对当前基础分枝杆菌代谢知识中的关键差距提出了一些看法，并从其他系统中吸取了一些经验教训。
