药物发现
铁载体
生物
结核分枝杆菌
药品
药物开发
计算生物学
药理学
遗传学
肺结核
生物信息学
细菌
医学
病理
作者
Mousumi Shyam,Deepak Shilkar,Gourav Rakshit,Venkatesan Jayaprakash
标识
DOI:10.1080/17460441.2022.2077328
摘要
Several decades of antitubercular drug discovery efforts have focused on novel antitubercular chemotherapies. However, recent efforts have greatly shifted toward countering extremely/multi/total drug-resistant species. Targeting the conditionally essential elements inside Mycobacterium is a relatively new approach against tuberculosis and has received lackluster attention. The siderophore, Mycobactin, is a conditionally essential molecule expressed by mycobacteria in iron-stress conditions. It helps capture the micronutrient iron, essential for the smooth functioning of cellular processes.The authors discuss opportunities to target the conditionally essential pathways to help develop newer drugs and prolong the shelf life of existing therapeutics, emphasizing the bottlenecks in fast-tracking antitubercular drug discovery.While the lack of iron supply can cripple bacterial growth and multiplication, excess iron can cause oxidative overload. Constant up-regulation can strain the bacterial synthetic machinery, further slowing its growth. Mycobactin synthesis is tightly controlled by a genetically conserved mega enzyme family via up-regulation (HupB) or down-regulation (IdeR) based on iron availability in its microenvironment. Furthermore, the recycling of siderophores by the MmpL-MmpS4/5 orchestra provides endogenous drug targets to beat the bugs with iron-toxicity contrivance. These processes can be exploited as chinks in the armor of Mycobacterium and be used for new drug development.
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