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.

Identificación de micobacterias no tuberculosas en pacientes VIH/SIDA por métodos convencionales y de fracciones de ácidos micólicos / Identification of non tuberculosis mycobacteria from HIV/AIDS patients by conventional methods and by study of mycolic acid fractions

Las micobacterias no tuberculosas son patógenos oportunistas capaces de producir infecciones pulmonares y extrapulmonares. El aumento de su incidencia se ha acelerado después de la aparición del Síndrome de Inmunodeficiencia Adquirida (SIDA). En este trabajo se estudiaron 40 cepas aisladas de pacientes infectados por el Virus de Inmunodeficiencia Humana, A los aislamientos con significación patogénica se le aplicó el estudio de los patrones de las fracciones de ácidos micólicos. Los resultados fueron: 9 Mycobacterium avium, 8 Mycobacterium fortuitum, 4 Mycobacterium flavescens, 4 Mycobacterium smegmatis, 3 Mycobacterium marinum, 4 Mycobacterium gastri, 2 Mycobacterium gordonae, 2 Mycobacterium chelonae, 1 Mycobacterium xenopi, 1 Mycobacterium phlei, 1 Mycobacterium triviale, y 1 Mycobacterium malmoense. Sólo 5 de estas cepas estaban asociadas a cuadros clínicos: 2 Mycobacterium avium (micobacteriosis diseminada y renal respectivamente), 1 Mycobacterium gordonae (lesiones en piel), 1 Mycobacterium fortuitum (linfadenitis submaxilar), 1 Mycobacterium malmoense (linfadenitis submaxilar). Las especies más frecuentemente aisladas fueron M. avium y M. fortuitum acorde con lo revisado en la literatura. La aplicación simultánea de las técnicas convencionales y el estudio de las fracciones de ácidos micólicos ha permitido obtener resultados más confiables por lo que recomendamos su aplicación en estos estudios.

Non tuberculosis mycobacteria are opportunist pathogens whose frequency in human infections has increased after the appearance of the Acquired Immunodefficiency Syndrome (AIDS). In this work we studied 40 strains isolated from patients infected by the Human Immunodefficiency Virus and isolates with pathogenic significance were further analyzed for diagnostic confirmation by the method that studies mycolic acid fractions. After identification, the results were: 9 Mycobacterium avium, 8 Mycobacterium fortuitum, 4 Mycobacterium flavescens, 4 Mycobacterium smegmatis, 3 Mycobacterium marinum, 4 Mycobacterium gastri, 2 Mycobacterium gordonae, 2 Mycobacterium chelonae, 1 Mycobacterium xenopi, 1 Mycobacterium phlei, 1 Mycobacterium triviale, and 1 Mycobacterium malmoense. Only five of these strains were associated to clinical symptoms: 2 Mycobacterium avium (disseminated and renal mycobacteriosis respectively), 1 Mycobacterium gordonae (skin lesions), 1 Mycobacterium fortuitum (submaxilar lymphoadenitis), and 1 Mycobacterium malmoense (submaxilar lymphoadenitis). The species most frequently isolated were: M. avium and M. fortuitum, in agreement with a bibliographic revision. The simultaneous application of conventional techniques and the study of mycolic acid allowed us to obtain more trustworthy results.