We investigated mutations in the genesIsoniazid (INH), a first-line antituberculosis drug, is bactericidal and has a simple chemical structure consisting of a pyridine ring and a hydrazide group. INH is a prodrug that enters actively growing tubercle bacilli by passive diffusion (2). The bifunctional bacterial enzyme catalase-peroxidase (KatG) converts INH to a range of oxygenated and organic toxic radicals that attack multiple targets in the mycobacterial cell (35,36,48). The best-characterized target of these radicals is the cell wall mycolic acid, but DNA, carbohydrates, lipids, and NAD metabolism may be targeted as well (16,36,50).The tuberculosis case rate in Brazil is the 15th highest in the world, with an estimated prevalence of 64 cases per 100,000 population; moreover, ϳ0.9% of the new cases are multidrug resistant (45). A recent nationwide investigation of primary INH resistance found a national frequency of 3.8% (29); however, the percentages varied greatly between geographic regions of the country.

Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC-MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority of species analyzed. The composition of the essential oil of Piper mosenii was described for the first time. The cytotoxicity of the essential oils was evaluated in peritoneal macrophages and the oils of P. rivinoides, P. arboretum, and P. aduncum exhibited the highest values, with cytotoxic concentration at 50% (CC 50 ) > 200 µg/mL. Both P. diospyrifolium and P. aduncum displayed activity against Leishmania amazonensis, and were more selective for the parasite than for the macrophages, with a selectivity index (SI) of 2.35 and >5.52, respectively. These SI values were greater than the 1 for the standard drug pentamidine. The antileishmanial activity of the essential oils of P. diospyrifolium and P. aduncum was described for the first time. P. rivinoides, P. cernuum, and P. diospyrifolium displayed moderate activity against the Mycobacterium tuberculosis H 37 Rv bacillus, with a minimum inhibitory concentration (MIC) of 125 µg/mL. These results are relevant and suggests their potential for therapeutic purposes. Nevertheless, further studies are required to explain the exact mechanism of action of these essential oils.

No abstract

These results contribute to the knowledge of the molecular mechanism of pyrazinamide resistance in Brazil and also expand the profile of pncA mutations worldwide. The MABA was successfully used to determine the MICs of pyrazinamide.