A 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.
Bibliographical noteFunding Information:
This work was funded by a National Institutes of Health (NIH) grant AI090048 (S.G.-T.), a grant from the Center for Chemical Genomics (CCG) at the University of Michigan (S.G.-T.), a grant from the Firland Foundation (S.G.-T.), as well as by startup funds from the College of Pharmacy at the University of Kentucky (S.G.-T. and O.V.T.). We thank Steve Vander Roest, Martha Larsen, and Paul Kirchhoff (CCG, University of Michigan) for help with HTS. We thank the staff of Sector 22 (SER-CAT) of the Advanced Photon Source at the Argonne National Laboratories for their assistance with the remote X-ray diffraction data collection.