Abordagem racional no planejamento de novos tuberculostáticos: inibidores da InhA, enoil-ACP redutase do M. tuberculosis: [revisão] / Rational approach in the new antituberculosis agent design: inhibitors of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis: [review]

Associada à disseminação da infecção causada pelo HIV, a tuberculose (TB) é considerada, atualmente, problema mundial de saúde pública devido às proporções que vem assumindo. A resistência micobacteriana aos fármacos utilizados na terapêutica é a principal causa da reincidência da TB. Diante deste quadro alarmante, o desenvolvimento de novos e seletivos fármacos anti-TB se faz urgente e necessário. A biossíntese de ácidos graxos é um processo bioquímico realizado por procariotos e eucariotos, o qual fornece precursores essenciais à montagem de componentes celulares importantes, tais como fosfolipídeos, lipoproteínas, lipopolissacarídeos, ácidos micólicos e envelope celular. As diferenças bioquímicas e funcionais entre o mecanismo biossintético de ácidos graxos em bactérias e mamíferos tornam-no alvo relevante ao planejamento de novos antibacterianos, mais seletivos e menos tóxicos. As enoil-ACP redutases são enzimas cruciais à etapa de alongamento de ácidos graxos, considerados produtos intermediários na biossíntese de ácidos micólicos - os principais componentes da parede celular micobacteriana. Portanto, tais enzimas são tidas como alvos moleculares no planejamento racional de novos tuberculostáticos. Avanços recentes no processo de descoberta de novos agentes anti-TB, particularmente os inibidores da enoil-ACP redutase, serão discutidos nesta revisão.

In conjunction with the spread of HIV infection, tuberculosis (TB) has been among the worldwide health threats. Mycobacteria resistance to the drugs currently used in the therapeutics is the main cause of TB resurgence. In view of this severe situation, the new and selective anti-TB design is of utmost importance. Fatty acid biosynthesis is a prokariontes and eucariontes biochemical process that supplies essential precursors for the assembly of important cellular components, such as phospholipids, lipoproteins, lipopolysaccharides, mycolic acids and cellular envelope. However, the biochemical and functional differences between the bacterial and mammals' fatty acid synthetic pathway have endowed the mycobacterial enzymes with distinct properties. These provide valuable opportunities for structure- or catalytic mechanism-based design of selective inhibitors as novel anti-TB drugs with improved properties. The enoyl-reductases are essential enzymes in the fatty acids elongation pathway towards the mycolic acids, the main mycobacteria cell wall constituents, biosynthesis and so they are potential targets to the rational new antimycobacteria drug design. This paper highlights recent approaches regarding the design of new anti-TB agents, particularly, the enoyl-ACP reductase inhibitors.

Pyridoxine for severe metabolic acidosis and seizures due to isoniazid [INH] overdose

Isoniazid [INH] overdose can be effectively treated, only if, suspected. Seizures and coma are due to INH unless proved otherwise in patients with access to the drug. Acute INH intoxication is characterized by a clinical triad consisting of metabolic acidosis resistant to treatment with sodium bicarbonate, seizure which may be fatal and refractory to standard anticonvulsant therapy, and coma. Pyridoxine is the specific antidote for INH overdose. We report a case of a 25-yr-old lady, who in a suicidal attempt ingested a toxic dose of INH resulting in status epilepticus and was successfully treated with pyridoxine [Vit B6]

Protective effect of N-acetylcysteine in isoniazid induced hepatic injury in growing rats.

Status of oxidative/antioxidative profile was the mechanistic approach to inumerate the nature of protection by N-acetylcysteine (NAC) in isoniazid (INH) exposed experimental animals. Analysis of lipid peroxidation, thiol levels, cytochrome P450, superoxide dismutase (SOD), catalase, glutathione peroxidase, reductase and transferase were estimated in liver along with the body and liver weight of animals and histological observations. Isoniazid exposure to animals resulted in no change in body and liver weights. Thiols, lipid peroxidation, catalase, SOD glutathione peroxidase, reductase, transferase and cytochrome P450 levels were altered with INH exposure. Supplementation of NAC with INH protected the animals against hepatotoxic reactions by minimizing the free radical induced tissue injury and overall maintenance of the endogenous scavengers of free radicals.

Isonicotinic acid hydrazide inhibits cell population growth during teratogenesis of chick embryo.

In chick embryos treated with a 4 hr pulse of 7.2 X 10(-5) M isonicotinic acid hydrazide (INH) the cell population growth is inhibited with an increased population doubling time. Teratogenised blastoderm cells complete their ongoing cell cycle and arrest in G1 phase. A chase with an equimolar concentration of pyridoxal-5-phosphate restores the growth rate after a lag of 4 hr equivalent to the duration of treatment with INH. Presumptive mesoblast cells invaginated through the primitive streak and neuroectoblast cells induced prior to the application of INH differentiate, while the teratogen inhibits morphogenesis and organization of organ primordia.