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

Autor: Tam B; Department of Chemistry , Ben-Gurion University of the Negev , Beer-Sheva , Israel . Email: akabayov@bgu.ac.il., Sherf D; Department of Chemistry , Ben-Gurion University of the Negev , Beer-Sheva , Israel . Email: akabayov@bgu.ac.il., Cohen S; Department of Chemistry , Ben-Gurion University of the Negev , Beer-Sheva , Israel . Email: akabayov@bgu.ac.il., Eisdorfer SA; Department of Chemistry , Ben-Gurion University of the Negev , Beer-Sheva , Israel . Email: akabayov@bgu.ac.il., Perez M; Department of Structural Biology , Weizmann Institute of Science , Rehovot , Israell., Soffer A; School of Computer and Electrical Engineering , Ben-Gurion University of the Negev , Israel., Vilenchik D; School of Computer and Electrical Engineering , Ben-Gurion University of the Negev , Israel., Akabayov SR; Department of Structural Biology , Weizmann Institute of Science , Rehovot , Israell., Wagner G; Department of Biological Chemistry and Molecular Pharmacology , Harvard Medical School , Boston , MA , USA., Akabayov B; Department of Chemistry , Ben-Gurion University of the Negev , Beer-Sheva , Israel . Email: akabayov@bgu.ac.il.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2019 Aug 06; Vol. 10 (38), pp. 8764-8767. Date of Electronic Publication: 2019 Aug 06 (Print Publication: 2019).
DOI: 10.1039/c9sc02520k
Abstrakt: 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 ( T 2 ) 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 IC 50 values, which were significantly improved over standard antibiotic drugs.
(This journal is © The Royal Society of Chemistry 2019.)
Databáze: MEDLINE
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