Document Detail

Identification of antituberculosis agents that target ribosomal protein interactions using a yeast two-hybrid system.
MedLine Citation:
PMID:  23045703     Owner:  NLM     Status:  MEDLINE    
Mycobacterium tuberculosis kills about 2 million people annually and antibiotic resistance is a cause of increased mortality. Therefore, development of new antituberculosis drugs is urgent for the control of widespread tuberculosis infections. For this purpose, we performed an innovative screen to identify new agents that disrupt the function of ribosomes in M. tuberculosis. Two bacterial ribosomal proteins L12 and L10 interact with each other and constitute the stalk of the 50S ribosomal subunit, which recruits initiation and elongation factors (EFs) during translation. Therefore, the L12-L10 interaction should be essential for ribosomal function and protein synthesis. We established a yeast two-hybrid system to identify small molecules that block the interaction between L12 and L10 proteins from M. tuberculosis. Using this system, we identified two compounds T766 and T054 that show strong bactericidal activity against tuberculosis but with low toxicity to mice and other bacterial strains. Moreover, using surface plasmon resonance (SPR) assay, we have demonstrated that these compounds bind specifically to L12 to disrupt L12-L10 interaction. Overproduction of L12 protein, but not L10, lowers the antibacterial activity of T766 and T054, indicating that the ribosome is likely the cellular target. Therefore, our data demonstrate that this yeast two-hybrid system is a useful tool to identify unique antituberculosis agents targeting the ribosomal protein L12-L10 interaction.
Yuan Lin; Yan Li; Yuanjun Zhu; Jing Zhang; Yongzhen Li; Xiao Liu; Wei Jiang; Shishan Yu; Xue-Fu You; Chunling Xiao; Bin Hong; Yanchang Wang; Jian-Dong Jiang; Shuyi Si
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-08
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-24     Completed Date:  2013-01-07     Revised Date:  2014-05-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17412-7     Citation Subset:  IM    
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MeSH Terms
Antitubercular Agents / metabolism,  pharmacology*
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects,  growth & development
Ribosomal Proteins / metabolism*
Saccharomyces cerevisiae / genetics*
Surface Plasmon Resonance
Two-Hybrid System Techniques
Grant Support
Reg. No./Substance:
0/Antitubercular Agents; 0/Ribosomal Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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