期刊
MICROORGANISMS
卷 9, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/microorganisms9030568
关键词
toxin-antitoxin system; structure-based drug discovery; antimicrobial candidate; stapled peptide
类别
资金
- Korea Drug Development Fund - Ministry of Science and ICT
- Ministry of Health and Welfare (Korea) [KDDF-201712-03]
- Ministry of Trade, Industry, and Energy
Optimizing candidate peptides based on structural information from TA systems can lead to novel and effective antimicrobial agents targeting Mycobacterium tuberculosis, exhibiting enhanced activity and cell permeability. This approach opens a new era for developing TB therapies by utilizing structural and biochemical information for new antibiotic targets.
The structure-function relationships of toxin-antitoxin (TA) systems from Mycobacterium tuberculosis have prompted the development of novel and effective antimicrobial agents that selectively target this organism. The artificial activation of toxins by peptide inhibitors can lead to the growth arrest and eventual death of bacterial cells. Optimizing candidate peptides by hydrocarbon alpha-helix stapling based on structural information from the VapBC TA system and in vitro systematic validation led to V26-SP-8, a VapC26 activator of M. tuberculosis. This compound exhibited highly enhanced activity and cell permeability owing to the stabilizing helical propensity of the peptide. These characteristics will increase its efficacy against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Similar approaches utilizing structural and biochemical information for new antibiotic targets opens a new era for developing TB therapies.
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