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

doi:10.1073/pnas.1302816110

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

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Abstract

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 highthroughput 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.

Original language	English (US)
Pages (from-to)	10282-10287
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	25
DOIs	https://doi.org/10.1073/pnas.1302816110
State	Published - Jun 18 2013

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Ramadoss, N. S., Alumasa, J. N., Cheng, L., Wang, Y., Li, S., Chambers, B. S., Chang, H., Chatterjee, A. K., Brinker, A., Engels, I. H., & Keiler, K. C. (2013). Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity. Proceedings of the National Academy of Sciences of the United States of America, 110(25), 10282-10287. https://doi.org/10.1073/pnas.1302816110

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abstract = "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 highthroughput 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.",

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

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Ramadoss, NS, Alumasa, JN, Cheng, L, Wang, Y, Li, S, Chambers, BS, Chang, H, Chatterjee, AK, Brinker, A, Engels, IH & Keiler, KC 2013, 'Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 25, pp. 10282-10287. https://doi.org/10.1073/pnas.1302816110

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T1 - Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity

AU - Ramadoss, Nitya S.

AU - Alumasa, John N.

AU - Cheng, Lin

AU - Wang, Yu

AU - Li, Sharon

AU - Chambers, Benjamin S.

AU - Chang, Hoon

AU - Chatterjee, Arnab K.

AU - Brinker, Achim

AU - Engels, Ingo H.

AU - Keiler, Kenneth C.

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AB - 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 highthroughput 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.

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

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