Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis

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.