5ICJ

Crystal structure of the Mycobacterium tuberculosis transcriptional repressor EthR2 in complex with BDM41420

Summary for 5ICJ

• Entry DOI: 10.2210/pdb5icj/pdb
• Descriptor: Probable transcriptional regulatory protein, 4,4,4-trifluoro-1-(3-phenyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)butan-1-one (3 entities in total)
• Functional Keywords: helix-turn-helix dna binding protein, tetr family, transcription, regulatory repressor, inhibitor, transcription repressor-inhibitor complex
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 48925.82

Authors

Wohlkonig, A.,Remaut, H.,Tanina, A.,Meyer, F.,Willand, N.,Baulard, A.R.,Wintjens, R. (deposition date: 2016-02-23, release date: 2017-04-26, Last modification date: 2024-01-10)

Primary citation

Blondiaux, N.,Moune, M.,Desroses, M.,Frita, R.,Flipo, M.,Mathys, V.,Soetaert, K.,Kiass, M.,Delorme, V.,Djaout, K.,Trebosc, V.,Kemmer, C.,Wintjens, R.,Wohlkonig, A.,Antoine, R.,Huot, L.,Hot, D.,Coscolla, M.,Feldmann, J.,Gagneux, S.,Locht, C.,Brodin, P.,Gitzinger, M.,Deprez, B.,Willand, N.,Baulard, A.R.
Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420.
Science, 355:1206-1211, 2017

PubMed Abstract: Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in , circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.

PubMed: 28302858
DOI: 10.1126/science.aag1006

Experimental method

X-RAY DIFFRACTION (2.4 Å)