Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity.

Nitya S Ramadoss, John N Alumasa, Lin Cheng, Yu Wang, Sharon Li, Benjamin S Chambers, Hoon Chang, Arnab K Chatterjee, Achim Brinker, Ingo H Engels, Kenneth C Keiler

Proceedings of the National Academy of Sciences of the United States of America 2013 Jun 18

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The trans-translation pathway for protein tagging and ribosome release plays a critical role for viability and virulence in a wide range of pathogens but is not found in animals. To explore the use of trans-translation as a target for antibiotic development, a high-throughput screen and secondary screening assays were used to identify small molecule inhibitors of the pathway. Compounds that inhibited protein tagging and proteolysis of tagged proteins were recovered from the screen. One of the most active compounds, KKL-35, inhibited the trans-translation tagging reaction with an IC50 = 0.9 µM. KKL-35 and other compounds identified in the screen exhibited broad-spectrum antibiotic activity, validating trans-translation as a target for drug development. This unique target could play a key role in combating strains of pathogenic bacteria that are resistant to existing antibiotics.

Citation

Nitya S Ramadoss, John N Alumasa, Lin Cheng, Yu Wang, Sharon Li, Benjamin S Chambers, Hoon Chang, Arnab K Chatterjee, Achim Brinker, Ingo H Engels, Kenneth C Keiler. Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity. Proceedings of the National Academy of Sciences of the United States of America. 2013 Jun 18;110(25):10282-7