Repository logo
 

A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.


Change log

Authors

Nikiforov, Petar O 
Surade, Sachin 
Blaszczyk, Michal 
Delorme, Vincent 
Brodin, Priscille 

Abstract

With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.

Description

Keywords

Crystallography, X-Ray, Ethionamide, Hydrophobic and Hydrophilic Interactions, Inhibitory Concentration 50, Molecular Structure, Mycobacterium tuberculosis, Repressor Proteins, Small Molecule Libraries, Structure-Activity Relationship

Journal Title

Org Biomol Chem

Conference Name

Journal ISSN

1477-0520
1477-0539

Volume Title

14

Publisher

Royal Society of Chemistry (RSC)
Sponsorship
Bill & Melinda Gates Foundation (via Foundation for the National Institutes of Health (FNIH)) (ABELL11HTB0)
Medical Research Council (MR/N501864/1)
European Commission (260872)
We also thank the Bill and Melinda Gates Foundation and the EU FP7 MM4TB Grant n°260872, the ERC-STG INTRACELLTB Grant n°260901, the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Feder (12001407 (D-AL) Equipex Imaginex BioMed) and the Région Nord Pas de Calais, France, for providing funding to support this work.