• Citer

Mutations in the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro selected PA-824 mutants of Mycobacterium tuberculosis.

par Hana L, Haver;Chua, Adeline;Pramila, Ghode;Lakshminarayana, Suresh SB;Singhal, Amit;Mathema, Barun;Wintjens, René ;Bifani, Pablo
Référence Antimicrobial agents and chemotherapy
Publication Publié, 2015-06

Article révisé par les pairs

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

Alleviating the burden of tuberculosis (TB) requires an understanding of the genetic basis that determines the emergence of drug resistant mutants. PA-824 (Pretonamid) is a bicyclic nitroimidazole class compound presently undergoing the phase III STAND clinical trial despite lacking identifiable genetic markers for drug-specific resistant Mycobacterium tuberculosis (Mtb). In the present study, we aimed to characterize the genetic polymorphisms of spontaneously generated PA-824 resistant mutant strains by surveying drug metabolism genes for potential mutations. Of the 183 independently selected PA-824 resistant Mtb mutants, 83% harbored a single mutation in one of five non-essential genes associated in either PA-824 pro-drug activation (ddn - 29%, fgd1 - 7%) or the tangential F420 biosynthetic pathway (fbiA - 19%, fbiB - 2%, fbiC - 26%). Crystal structure analysis indicated that identified mutations were specifically located within the protein catalytic domain that would hinder the activity of the enzymes required for pro-drug activation. This systematic analysis conducted of resistant genotypes to PA-824 may contribute to future efforts in monitoring clinical strain susceptibility with this new drug therapy.