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 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.
Sullivan
Todd J
TJ
Department of Chemistry, SUNY Stony Brook, Stony Brook, New York 11794-3400, USA.
Truglio
James J
JJ
Boyne
Melissa E
ME
Novichenok
Polina
P
Zhang
Xujie
X
Stratton
Christopher F
CF
Li
Huei-Jiun
HJ
Kaur
Tejinder
T
Amin
Amol
A
Johnson
Francis
F
Slayden
Richard A
RA
Kisker
Caroline
C
Tonge
Peter J
PJ
D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors; D006801:Humans; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; D044943:Fatty Acid Desaturases; C085257:InhA protein, Mycobacterium