Mechanism for the Pyridoxal Neutralization of Isoniazid Action on Mycobacterium tuberculosis

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In Sauton's synthetic liquid medium, 10 μg of pyridoxal per ml completely protected Mycobacterium tuberculosis (H37Ra) from the effects of a minimal inhibitory concentration of isoniazid (0.01 μg/ml). 14C-labeled isoniazid was employed to study the nature of this protective effect. Uptake of the drug by cells in a Sauton environment containing 0.01 μg of 14C-isoniazid per ml was inhibited 20 to 40% by 10 μg of pyridoxal per ml during the early hours of drug exposure. A stronger inhibition of uptake resulted when labeled isoniazid and pyridoxal were increased to 0.1 μg/ml and 50 to 100 μg/ml, respectively. Further studies revealed that certain Sauton nutrients are required to achieve this effect. When l-asparagine or salts (MgSO4 and ferric ammonium citrate) or both were deleted from the menstruum, pyridoxal did not inhibit isoniazid incorporation by the tubercle bacilli. Pyridoxal also failed to inhibit uptake when (NH4)2SO4 was substituted for l-asparagine. Growth experiments in Sauton's medium modified to contain (NH4)2SO4 instead of l-asparagine were consistent with the latter finding. Pyridoxal did not prevent isoniazid growth inhibition in this medium. It is postulated that a large excess of pyridoxal in Sauton's medium protects tubercle bacilli from the effects of isoniazid through formation of an extracellular complex involving drug, vitamin, and certain medium constituents, thereby reducing the level of isoniazid available to the cells.

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