Microbial transformation of isonicotinic acid hydrazide and isonicotinic acid bySarcina sp

Metabolism of isonicotinic acid and isoniazid bySarcina sp. led to the formation of two metabolites which were characterised as 2-hydroxyisonicotinic acid and citrazinic acid. The blue pigment formed during fermentation was shown to be derived from the auto-oxidation of citrazinic acid. 2-Oxo-glutarate accumulated as the major keto acid when isonicotinic acid or isonicotinic acid hydrazide metabolism was inhibited by 1 mM sodium arsenite. Isonicotinic acid, 2-hydroxy-isonicotinic acid and 2-oxo-glutarate were oxidised by isonicotinic acid hydrazide or isonicotinic acid-grown cells; citrazinic acid was, however, not oxidised. Isoniazid hydrazine hydrolase, isonicotinic acid and 2-hydroxyisonicotinic acid hydroxylases were detected in the cell-free extract ofSarcina sp. grown on isonicotinic acid hydrazide or isonicotinic acid. Communication no. 2427from Central Drug Research Institute, Lucknow.     

Coccidioidomycosis; treatment with isonicotinic acid hydrazide

Since coccidioidal granulomas are histologically indistinguishable from tuberculous granulomas, a long course of isonicotinic acid hydrazide therapy was tried experimentally in three cases of coccidioidomycosis, with good results. In two cases the disease was far advanced and prognosis poor before INH therapy was begun. In one case the disease was mild and symptoms abated after a short course of small doses of INH. It recurred when INH therapy was discontinued, and again resolved when larger doses of INH were given over a longer period.INH seemed to have an effect on appetite also, although the patients were taking B-complex vitamins both before and during INH treatment. The three patients ill with coccidioidomycosis averaged a weight gain of four and a half pounds a month during the period of INH therapy. Six well persons who were underweight and lacked appetite were given INH without other drugs, and they then had an increase in appetite and in weight.     

Different oxidative pathways of isonicotinic acid hydrazide and its meta-isomer,nicotinic acid hydrazide

• 1.1. Superoxide was generated during the auto-oxidation of the antituberculous drug, isonicotinic acid hydrazide (INH), but not with its meta-isomer, nicotinic acid hydrazide (NH). During Fe²⁺-stimulated oxidation of INH and NH, aromatic hydroxylation occurred which was inhibited by the chelating agent, phytic acid.
• 2.2. A mixture of myeloperoxidase (MPO) and a hydrazide induced formation of compound III (oxyperoxidase) and aromatic hydroxylation which was stimulated by phytic acid. INH was considerably more potent than NH.
• 3.3. Co-oxidation of a hydrazide and thyroxine (T₄) in the MPO system resulted in the formation of a pink-coloured product (maximum absorbance at 504 nm) which was more stable with NH than with INH.
• 4.4. The hydrazides and Cl⁻ acted synergistically on MPO haem modification when co-oxidised in the MPO-H₂O₂ system. INH was more destructive than NH.
• 5.5. The different oxidative pathways of the hydrazides are consistent with the fact that an acyl intermediate of INH, unlike that of NH, is resonance stabilized.