Pyridomycin bridges the NADH- and substrate-binding pockets of the enoyl reductase InhA

Abstract

Pyridomycin, a natural product with potent antituberculosis activity, inhibits a major drug target, the InhA enoyl reductase. Here, we unveil the co-crystal structure and unique ability of pyridomycin to block both the NADH cofactor- and lipid substrate-binding pockets of InhA. This is to our knowledge a first-of-a-kind binding mode that discloses a new means of InhA inhibition. Proof-of-principle studies show how structure-assisted drug design can improve the activity of new pyridomycin derivatives.

Mycobacterium Tuberculosis Evolutionary Pathogenesis and its Putative Impact on Drug Development

“…One striking example is the identification of the enoyl reductase InhA as the drug target of the natural compound pyridomycin [54], which bridges the NADH-and substrate-binding pockets of the enzyme and thus inhibits InhA in a different way than the first-line drug isoniazid, which is a prodrug and needs activation by KatG in order to form the active isonicotinic acyl-NADH complex. As a result, pyridomycin is also active on the most frequently encountered isoniazid-resistant M. tuberculosis strains, which opens new perspectives for drug development [55].…”

The molecular biology of mycobacterial trehalose in the quest for advanced tuberculosis therapies

“…The synthetic drug isoniazid is one of the frontline anti-mycobacterials that inhibits the NADH-dependent enoyl reductase (InhA), an essential enzyme of the cytoplasmic FAS-II complex involved in MAs biosynthesis and one of the best validated targets for TB therapy (Morbidoni et al, 2006;Rozwarski et al, 1998). Remarkably, the natural antimicrobial compound pyridomycin produced by strains of Streptomyces and Dactylosporangium also selectively blocks InhA substratebinding pockets and may be used as a strategy to overcome isoniazid resistance (Hartkoorn et al, 2014). Ethambutol is a bacteriostatic drug administered in combination with isoniazid (and with rifampicin and pyrazinamide) as the first-line therapeutic option for drug-susceptible TB and it disrupts the assembly of AG, a crucial structural network of the cell wall, by inhibiting a key arabinosyltransferase activity (EmbA and EmbB) (Stehr et al, 2014).…”

Totalsynthese von Nosiheptid

“…[263] Bei einer Überlagerung der Strukturen des InhA-PyridomycinKomplexes mit der des InhA-Substrat-NADH-Komplexes (Abbildung 5.2) wird ersichtlich, dass Pyridomycin (gelb) sowohl in der Bindungstasche des Substrats (Fettsäure, blau) als auch in der des Coenzyms (NADH, rot) bindet. [264] Abbildung 5.2: Vergleich der Bindungstaschen von Substrat und Coenzym mit Pyridomycin in InhA.…”

“…[264] Damit ist Pyridomycin mit seinem einzigartigen Bindungsmodus, das einzige Beispiel für einen Inhibitor, der effektiv die NADH-Bindung blockiert, jedoch kein NADH-Mimetikum ist. [264] Trotz seiner hohen in vitro-Aktivität zeigte die Substanz in Tiermodellen keine Aktivität, wofür die schlechten pharmakokinetischen Eigenschaften der Substanz verantwortlich gemacht wurden. [265] hat.…”