A new 'golden age' for the antitubercular target InhA.
The increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis is the main contributing factor in unfavorable outcomes in the treatment of tuberculosis. Studies suggest that direct inhibitors of InhA, an enoyl-ACP-reductase, might yield promising clinical candidates that can be developed into new antitubercular drugs. In this review, we describe the application of different hit-identification strategies to InhA, which clearly illustrate the druggability of its active site through distinct binding mechanisms. We further characterize four classes of InhA inhibitors that show novel binding modes, and provide evidence of their successful target engagement as well as their in vivo activity.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
Kaja
K
Rožman
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
Izidor
I
Sosič
Diseases of the Developing World, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
Raquel
R
Fernandez
GlaxoSmithKline Medicines Research Centre, Stevenage, Herfordshire SG1 2NY, UK.
Robert J
RJ
Young
Diseases of the Developing World, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
Alfonso
A
Mendoza
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.
Stanislav
S
Gobec
Diseases of the Developing World, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain. Electronic address: lourdes.p.encinas-prieto@gsk.com.
Lourdes
L
Encinas
D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D003461:Crystallography; D015195:Drug Design; D006801:Humans; D007265:Inhibins / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism
D000995:Antitubercular Agents; C094377:inhibin-alpha subunit; D007265:Inhibins