THE MOLECULAR MECHANISMS OF DRUG-RESISTAN CE IN MYCOBACTERIUM-TUBERCULOSIS

The potentially deadly association between AIDS and tuberculosis repre sents an enormous public health problem which has been compounded by t he emergence of strains of M. tuberculosis resistant to two, or more, frontline drugs. It is now known that, as in other eubacteria, resista nce to rifampicin, streptomycin and fluoroquinolones results from miss ense mutations to essential chromosomal genes encoding the drug target s. In contrast, at least two novel mechanisms are responsible for resi stance to the potent tuberculocidal drug, isoniazid. High level resist ance is associated with mutations which inactivate the katG gene, or r esult in greately reduced activity of its product, the hem-containing enzyme catalase-peroxidase which is believed to activate the drug insi de the bacterium. Lower resistance levels, and cross-resistance to eth ionamide, result from over-expression of the inhA gene, encoding a nov el fatty acid synthase that may be involved in mycolic acid production . Unlike for many bacteria, multidrug resistance is not due to the acq uisition of resistance plasmids or transposons but to the accumulation of mutations in the genes encoding the respective drug targets.