High Affinity InhA Inhibitors with Activity against Drug-Resistant Strains of Mycobacterium tuberculosis

Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a K′i value of 1 nM for InhA and MIC99 values of 2–3 µg mL−1 (6–10 µM) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9–12-fold increase in MIC99, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl diphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activati...