Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) of: M. tuberculosis

Benjamin Tam; Dror Sherf; Shira Cohen; Sarah Adi Eisdorfer; Moshe Perez; Adam Soffer; Dan Vilenchik; Sabine Ruth Akabayov; Gerhard Wagner; Barak Akabayov

doi:10.1039/c9sc02520k

Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) of: M. tuberculosis

Benjamin Tam, Dror Sherf, Shira Cohen, Sarah Adi Eisdorfer, Moshe Perez, Adam Soffer, Dan Vilenchik, Sabine Ruth Akabayov, Gerhard Wagner, Barak Akabayov

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T₂) and computational chemistry approaches, we have obtained improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC₅₀ values, which were significantly improved over standard antibiotic drugs.

Original language	English
Pages (from-to)	8764-8767
Number of pages	4
Journal	Chemical Science
Volume	10
Issue number	38
DOIs	https://doi.org/10.1039/c9sc02520k
State	Published - 1 Jan 2019

ASJC Scopus subject areas

General Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) of: M. tuberculosis",

abstract = "M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50 values, which were significantly improved over standard antibiotic drugs.",

author = "Benjamin Tam and Dror Sherf and Shira Cohen and Eisdorfer, {Sarah Adi} and Moshe Perez and Adam Soffer and Dan Vilenchik and Akabayov, {Sabine Ruth} and Gerhard Wagner and Barak Akabayov",

note = "Funding Information: This research was supported by Grant No. 2016142 from the United States-Israel Binational Science Foundation (BSF) and the IMTI (TAMAT)/Israel Ministry of Industry–KAMIN Program, Grant No. 59081. The authors would like to thank Profs. Jack Cohen and Ira Weinstock (BGU) for helpful discussions. Publisher Copyright: {\textcopyright} 2019 The Royal Society of Chemistry.",

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doi = "10.1039/c9sc02520k",

language = "English",

volume = "10",

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AU - Tam, Benjamin

AU - Sherf, Dror

AU - Cohen, Shira

AU - Eisdorfer, Sarah Adi

AU - Perez, Moshe

AU - Soffer, Adam

AU - Vilenchik, Dan

AU - Akabayov, Sabine Ruth

AU - Wagner, Gerhard

AU - Akabayov, Barak

N1 - Funding Information: This research was supported by Grant No. 2016142 from the United States-Israel Binational Science Foundation (BSF) and the IMTI (TAMAT)/Israel Ministry of Industry–KAMIN Program, Grant No. 59081. The authors would like to thank Profs. Jack Cohen and Ira Weinstock (BGU) for helpful discussions. Publisher Copyright: © 2019 The Royal Society of Chemistry.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50 values, which were significantly improved over standard antibiotic drugs.

AB - M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50 values, which were significantly improved over standard antibiotic drugs.

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VL - 10

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JO - Chemical Science

JF - Chemical Science

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ER -

Discovery of small-molecule inhibitors targeting the ribosomal peptidyl transferase center (PTC) of: M. tuberculosis

Abstract

ASJC Scopus subject areas

UN SDGs

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