Discovery and Optimization of Two Eis Inhibitor Families as Kanamycin Adjuvants against Drug-Resistant <i>M. tuberculosis</i>

Drug-resistant tuberculosis (TB) is a global threat and innovative approaches such as using adjuvants of anti-TB therapeutics are required to combat it. High-throughput screening yielded two lead scaffolds of inhibitors of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) acetyltransferase Eis, whose upregulation causes resistance to the anti-TB drug kanamycin (KAN). Chemical optimization on these scaffolds resulted in potent Eis inhibitors. One compound restored the activity of KAN in a KAN-resistant <i>Mtb</i> strain. Model structures of Eis-inhibitor complexes explain the structure–activity relationship