Mathematical models have indicated that the relative fitness of drug resistant M.tb.
strains is the most important determinant when predicting the spread and epidemic potential of MDR- and XDR-TB2, 22
. Here, we have presented a possible mechanism of INH resistance, i.e.
, loss of sigI
and the associated SigI-dependent katG
expression. The ΔsigI
mutant did not exhibit diminished growth or virulence within mouse infection models, and in fact our data demonstrate that this mutant strain was more virulent than wild-type M.tb.
under the conditions tested. Furthermore, we have shown that the loss of sigI
results in increased bacterial survival in the presence of INH, indicating an in vivo
role for SigI in INH resistance. These findings could have significant implications for the spread of drug resistant M.tb.
Recently, Ando and colleagues have characterized INH-resistant human clinical isolates of M.tb.
. In their analysis of 108 INH-resistant isolates, they identified three unique mutations in the intergenic region upstream of katG
in 4% of the isolates. Three of these isolates did not contain additional mutations in the examined sequences (katG, inhA
promoter, aphC, ndh
), while one isolate also contained a mutation in the inhA
promoter region. These recent findings indicate that changes in the katG
promoter sequence can affect resistance to INH, and that this mode of INH resistance is relevant in human TB. While the putative SigI binding site that we identified was not mutated in these INH-resistant strains, this work by Ando et al.
indicates that alterations in the katG
promoter region influence susceptibility to INH. Thus, these findings support our hypothesis that SigI-mediated transcription of katG
may be is associated with M.tb.
susceptibility to INH.
lacking KatG function exhibits attenuated fitness for growth compared to wild-type M.tb.
, a second compensatory mutation has been identified which results in a regain of fitness, namely mutations in the ahp
gene, which encodes a peroxidase12
. Therefore, the generation of INH-resistance through this mechanism can be thought of as a two-step process whereby the initial katG
mutation is associated with a fitness loss, followed by a secondary, compensatory mutation in ahp
, which may increase the ability of the drug-resistant strain to survive in the community. In this communication, we have described an alternative pathway towards INH resistance in which a step towards drug (or multidrug) resistance, i.e.
, mutation of sigI
, is not associated with a fitness cost.