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

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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.

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

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Publication details

The article was received on 23 May 2019, accepted on 05 Aug 2019 and first published on 06 Aug 2019


Article type: Edge Article
DOI: 10.1039/C9SC02520K
Chem. Sci., 2019, Advance Article
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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

    B. Tam, D. Sherf, S. Cohen, S. A. Eisdorfer, M. Perez, A. Soffer, D. Vilenchik, S. R. Akabayov, G. Wagner and B. Akabayov, Chem. Sci., 2019, Advance Article , DOI: 10.1039/C9SC02520K

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