The molecular basis of isoniazid resistance in Mycobacterium tuberculosis.

نویسندگان

  • B Heym
  • B Saint-Joanis
  • S T Cole
چکیده

Isoniazid, the hydrazide of isonicotinic acid, was synthesized for the first time in 1912 by two Czech scientists, but its powerful antituberculous activity was detected only in 1951, and the discovery of isoniazid was a milestone in the chemotherapy of tuberculosis. Its activity is excellent against species of the Mycobacterium tuberculosis complex (M. tuberculosis, Mycobacterium bovis, Mycobacterium bovis BCG and Mycobacterium africanum), but it shows no or very little activity against non-tuberculous mycobacteria. The mode of action of isoniazid has been the subject of intensive studies, and beyond pleiotropic effects like the inhibition of protein and nucleic acid synthesis, the most constant finding was the loss of acid-fastness of the tubercle bacilli probably as a result of the inhibition of the synthesis of mycolic acids, the long-chained, branched fatty acids found in the cell wall. As these are confined essentially to the mycobacteria they represent a selective target for antimycobacterial drugs. Another hypothesis on the mode of action of isoniazid, originating from the chemical structure of isoniazid which is very similar to that of nicotinamide, aimed at the metabolism of nicotinamide adenine dinucleotide (NAD) which is an important cofactor of many enzyme systems in the bacterial cell. It was observed that isoniazid induced an activation of the mycobacterial NADase, followed by a diminution of the intracellular NAD concentration which could explain the pleiotropic effects on the mycobacterial cell by isoniazid. Nevertheless, this hypothesis did not allow an explanation of resistance to isoniazid, as the effects on NAD were identical in isoniazid susceptible and resistant strains of M. tuberculosis.

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عنوان ژورنال:
  • Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

دوره 79 4  شماره 

صفحات  -

تاریخ انتشار 1999