5iv0
Crystal structure of Eis from Mycobacterium tuberculosis in complex with sulfonamide inhibitor 39 and coenzyme ACrystal structure of Eis from Mycobacterium tuberculosis in complex with sulfonamide inhibitor 39 and coenzyme A
Structural highlights
Function[EIS_MYCTO] May participate in pathogenesis, possibly by enhancing survival of the bacteria in host macrophages during infection. Publication Abstract from PubMedA two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB. Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis.,Garzan A, Willby MJ, Green KD, Gajadeera CS, Hou C, Tsodikov OV, Posey JE, Garneau-Tsodikova S J Med Chem. 2016 Dec 8;59(23):10619-10628. Epub 2016 Nov 22. PMID:27933949[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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