Relationship between the uptake of isoniazid and its action on in vivo mycolic acid synthesis in Mycobacterium tuberculosis

Abstract

A direct relationship was established between the rate of uptake of isoniazid and the action of this drug on in vivo mycolic acid synthesis in Mycobacterium tuberculosis H37Ra. The rate of uptake of isoniazid increased linearly with its external concentration and appeared to reach a maximal value of 52 pmoles per hr per 10(9) cells at an external concentration of about 13 mum. Correspondingly, the rate of inhibition of mycolic acid synthesis increased with the rise in the rate of uptake of the drug. A 50% inhibition of mycolic acid synthesis occurred when the uptake of isoniazid reached 5.2 pmoles per 10(9) cells. Calculations showed that this level of drug uptake represents an internal cellular concentration of 9 mum. These results show clearly that the action of isoniazid on the mycolate synthetase system of M. tuberculosis is rapid and that this enzyme system is highly sensitive to the drug.