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

Citations Over TimeTop 10% of 2006 papers

Abstract

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 Ki' value of 1 nM for InhA and MIC99 values of 2-3 microg mL(-1) (6-10 microM) 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 activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.

Related Papers

• → Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations(2018)124 cited
• → ISONIAZID - MONORESISTANT TUBERCULOSIS IN BULGARIA(2020)3 cited
• → Detection of Genetic mutations in inhA and katG for Isoniazid and its Association with Rifampicin Resistance in Tuberculosis Confirmed by Line Probe Assay-its Rationality or Isoniazid Prophylaxis Empirical or DST Guided(2019)1 cited
• → Study of mutations associated with isoniazid resistance in clinical Mycobacterium tuberculosis strains from Tehran and Isfahan province tuberculosis centers by PCR and RFLP(1383–4)(2008)
• In vitro minimum inhibitory concentration of Mycobacterium tuberculosis isoniazid-resistant gene mutants(2012)