Structural highlights
Function
[ETHR_MYCTO] Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).
Publication Abstract from PubMed
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.
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.,Nikiforov PO, Surade S, Blaszczyk M, Delorme V, Brodin P, Baulard AR, Blundell TL, Abell C Org Biomol Chem. 2016 Jan 25. PMID:26806381[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nikiforov PO, Surade S, Blaszczyk M, Delorme V, Brodin P, Baulard AR, Blundell TL, Abell C. A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters. Org Biomol Chem. 2016 Jan 25. PMID:26806381 doi:http://dx.doi.org/10.1039/c5ob02630j
