MOLECULAR GENETICS OF FLUOROQUINOLONE RESISTANCE AND THE STRUCTURES OF KEY PYRIMIDINE BIOSYNTHESIS PATHWAY ENZYMES FROM MYCOBACTERIUM TUBERCULOSIS

Abstract

ALLELIC DIVERSITY OF FQ (FLUOROQUINOLONE)-RESISTANT MYCOBACTERIUM TUBERCULOSIS (MTB) MUTANTS WAS ANALYZED TO UNDERSTAND THE BASIS OF MUTANT SELECTION. NEWER FQS EXHIBITED HIGHEST POTENCY AND LOWEST MUTATION FREQUENCY. ENRICHMENT OF DNA GYRASE VARIANTS DEPENDED ON THE FQ TYPE AND CONCENTRATION USED (HIGHER CONCENTRATIONS SELECTED HIGH-LEVEL RESISTANT MUTANTS). LOW-LEVEL RESISTANT MUTANTS SHOWED INCREASED MICS EMPHASIZING THEIR IMPORTANCE IN CLINICAL SETUP. IMPORTANTLY, WHILE FQS EXHIBITED CROSS-RESISTANCE, MUTANT PREVENTION CONCENTRATION WAS ATTAINABLE, WHICH COULD BE EXPLORED TO LIMIT EMERGENCE OF RESISTANCE. CONCOMITANTLY, WE IDENTIFIED PROBABLE MTB TARGET ENZYMES FROM PYRIMIDINE BIOSYNTHESIS PATHWAY, WITH URACIL PHOSPHORIBOSYLTRANSFERASES (UPRTASES) ACTIVITY NAMELY, MTUPRT AND PYRR. HERE WE REPORT STRUCTURES OF MTUPRT AND PYRR-5-FLUOROURACIL COMPLEX. URACIL (UPRTASE SUBSTRATE) ANALOGUE, 5FU, HAS ANTI-TUBERCULOUS ACTIVITY. 5FU SELECTED MUTANTS HARBOR CONSERVED OR SUBSTRATE BINDING S