EFFECT OF INHA AND KATG ON ISONIAZID RESISTANCE AND VIRULENCE OF MYCOBACTERIUM-BOVIS

Isoniazid (INH) resistance of the Mycobacterium tuberculosis Complex ( MtbC) is associated with both loss of catalase activity and mutation o f the inhA gene. However, the relative contributions of these changes to resistance and to the loss of virulence for guineapigs is unknown. In this study, a virulent strain of Mycobacterium bovis, a member of t he MtbC, was exposed to increasing concentrations of INH. Two INH-resi stant strains were produced which had lost catalase activity. Strain W Ag405, which had a higher resistance to INH, also had a mutation in th e inhA gene. This demonstrated that loss of catalase activity and muta tion of inhA had a cumulative effect on INH resistance. When a functio nal katG gene was integrated into the genome of WAg405 the INH resista nce was greatly reduced. This indicated that most of the resistance ha d been caused by loss of catalase activity. While the parent INH-sensi tive strain was virulent for guinea-pigs, the INH-resistant strains we re significantly less virulent. Integration of a functional katG gene into the most resistant strain restored full virulence. This clearly e stablished that katG is a virulence factor for M. bovis and that mutat ion of the inhA gene has no effect on virulence.