Intermediary metabolism influences isoniazid sensitivity

Our genetic data indicate that the NADH oxidation systems influence isoniazid sensitivity. The Mdh enzyme of the M. tuberculosis complex is highly active at oxidizing NADH, and expression of this enzyme confers increased isoniazid sensitivity to M. smegmatis, a species that otherwise does not have this enzyme (Table 1). We suggest that Mdh enzyme may contribute to the extreme isoniazid sensitivity of M. tuberculosis, which is about 100-fold more sensitive than M. smegmatis. Although others have suggested that the exquisite isoniazid sensitivity of M. tuberculosis is due to a species-specific isoniazid target (Mdluli et al 1996), differences in metabolic functions (the KatG enzyme, peroxide concentrations and the NADH oxidation systems) may fully explain the different sensitivities of M. tuberculosis and M. smegmatis.

TABLE 1 Correlation between isoniazid sensitivity and NADH oxidation by Ndh or Mdh in Mycobacterium smegmatis

Strain genotype*

Isoniazid sensitivity

(MIC ßg/ml)

Ndh act.

ivity0 Mdh activity^

ndh+/-

5

40

2

ndh-4/-

>100

1

10

ndh-4/ndh (Mycobacterium tuberculosis)

2.5

150

1

ndh-4/mdh (Mycobacterium bovis)

1

2

10 000

*ndb chromosome allele/plasmid gene.

bActivity is the rate of NADH oxidation (mol/min permg X 107) in the presence of menadione as an electron acceptor. For experimental conditions see Miesel et al (1998).

cRate of NADH oxidation (mol/min permg X 107) in the presence of oxaloacetate as an electron acceptor. MIC, minimal inhibitory concentration.

*ndb chromosome allele/plasmid gene.

bActivity is the rate of NADH oxidation (mol/min permg X 107) in the presence of menadione as an electron acceptor. For experimental conditions see Miesel et al (1998).

cRate of NADH oxidation (mol/min permg X 107) in the presence of oxaloacetate as an electron acceptor. MIC, minimal inhibitory concentration.

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