Virulence in isoniazid-resistant clinical isolates of Mycobacterium tuberculosis from south India

Isoniazid, is the only antituberculous drug for which the relation between lack of virulence and acquisition of resistance was associated. INH-resistant mutants were shown to contain defective katG gene. Classical studies showed that INH-resistant south Indian isolates have lower virulence in guinea pigs and higher susceptibility to H2O2. It is of interest to assess the virulence in south Indian clinical mutants of KatG (catalase-peroxidase enzyme) associated with INH resistance. Five INH-resistant clinical isolates were selected on the basis of mutation in katG gene. Mutant isolates were used for infecting macrophage cell line (THP-1) and for the assessment of enzyme activity.  In comparison to control H37Rv, Ser315Thr mutant exhibits similar virulence and reduction (4% and 17%) in catalase (C) and peroxidase (P) activity. For the mutants, Ser315Iso and Ser315Arg, the virulent nature was slightly reduced with 3% and 2%, and significant reduction was observed in the C (50%; 47%) and P (36%; 43%) activity respectively. Ser315Asn indicates 4% reduction in virulence with significant reduction in C (56%) and P (64%) activity. Asn138Ser mutant displayed low-level virulence, CP activity showed 47% and 56% reduction. The results indicate that similar level of virulence in all the mutants except Asn138Ser which showed relatively low-level whereas a significant decrease in C and P activity was observed in all mutants except Ser315Thr. The study suggests despite the fact that all mutants do not compromise survival or virulence yet provides INH resistance.