Mechanisms of action of isoniazid

For decades after its introduction, the mechanisms of action of the front-line antituberculosis therapeutic agent isoniazid (INH) remained unclear. Recent developments have shown that peroxidative activation of isoniazid by the mycobacterial enzyme KatG generates reactive species that form adducts with NAD(+) and NADP(+) that are potent inhibitors of lipid and nucleic acid biosynthetic enzymes. A direct role for some isoniazid-derived reactive species, such as nitric oxide, in inhibiting mycobacterial metabolic enzymes has also been shown. The concerted effects of these activities - inhibition of cell wall lipid synthesis, depletion of nucleic acid pools and metabolic depression - drive the exquisite potency and selectivity of this agent. To understand INH action and resistance fully, a synthesis of knowledge is required from multiple separate lines of research - including molecular genetic approaches, in vitro biochemical studies and free radical chemistry - which is the intent of this review.     

Effect of ammonium salt on enzymes of ammonium assimilation in maize seedlings

Glutamate dehydrogenase (GDH E.C. 1.4.1.2.4), glutamine synthetase (GS E.C. 6.3.1.2) and glutamate synthase (glutamine oxoglutarate amino transferase, GOGAT E.C. 2.6.1.53) activities, protein and organic nitrogen contents and growth of roots and shoots of maize seedlings raised in dark at 25±2°C in half strength Hoagland’s solution containing different ammonium salts as source of nitrogen, were determined to assess the contribution of alternate pathways in ammonium assimilation. Ammonium nitrate or in some cases ammonium chloride appeared to be the best source for both root and shoot growth and for increase in protein, total nitrogen and the enzymes of ammonium assimilation. In roots, NH₄-nitrogen appeared to be assimilated by both GDH as well as GS-GOGAT pathways specially in the dark grown seedlings, while in shoots it was primarily by GS-GOGAT pathway.     

Chromosome-damaging action of isoniazid and thiacetazone on human lymphocyte cultures in vivo

Summary Antitubercular drugs in general are given in various combinations, one being isoniazid and thiacetazone. In the present study, was evaluated the in vivo chromosome-damaging effects of a combination of these two drugs in 72 h lymphocyte cultures.Chromosome aberrations were significantly increased in the patients treated with INH and thiacetazone as compared with two types of controls: (1) tuberculosis patients before starting the drug treatment and (2) individuals from the general population. The most frequently observed aberrations were chromatid breaks and gaps.It has been shown that individually, isoniazid may not be clastogenic on human chromosomes in therapeutic doses. The effects of thiacetazone on human chromosomes are not known. Consequently, the enhancement in chromosomal aberrations in the drug-exposed patients may be due to a synergistic effect of isoniazid and thiacetazone or to the clastogenic effects of thiacetazone alone.     

Synthesis of a quaternary polyprenyl ammonium salt

Reaction of primary C(55)-allylic alcohol moraprenol (WT(3)C(7-9)-OH, a polyprenol from mulberry leaves) with triethylamine in the presence of phosphorus oxychloride leads to a quaternary ammonium chloride with a good yield (72%) and high cis-stereoselectivity of the terminal isoprene unit. Cationic polyprenyl derivatives may be useful for transfection and immunological studies.     

Enhanced biodegradation of a hard bis-quaternary ammonium salt

Bacterial strains with a high biodegradation potential were isolated from activated sludge. Their ability to decompose the hard bis-quaternary ammonium salt FB was determined by the method of chemical oxygen demand (COD) in a mineral medium, where the compound FB was the only source of carbon. The COD values were very low after 21 d and in the course of this period they reached zero level twice. The contribution of adsorption to decrease the COD value was small. The maximum COD decrease was accompanied by an increase of cell respiration. It is suggested that FB is effectively decomposed in spite of the fact that according to its structure it is a typical hard detergent.     

Combined action of isoniazid and para-aminosalicylic acid in vivo on human chromosomes in lymphocyte cultures

Summary Two antitubercular drugs, viz., isoniazid (INH) and para-aminosalicylic acid (PAS), in combination, were evaluated for their in vivo clastogenic effects on human lymphocyte chromosomes. Lymphocyte cultures from tuberculosis patients taking a therapeutic dose of INH and PAS for a period of not less then 3 months and from two sets of controls were used: (1) newly diagnosed tuberculosis patients who were not yet under therapy and (2) healthy individuals from the general population. Chromosome aberration frequency was very significantly increased in the patients exposed to combined INH and PAS therapy as compared with controls. The most frequently observed aberrations were chromatid breaks and gaps. Isoniazid, the major antituberculosis drug, has been reported not to be clastogenic by itself. However, we observed that the INH-PAS combination commonly used in therapy was clastogenic. From this observation it may be concluded that INH and PAS act synergistically in producing chromosomal aberrations.