RESUMEN
Acquired azole resistance in opportunistic fungi causes severe clinical problems in immunosuppressed individuals. This study investigated the molecular mechanisms of azole resistance in clinical isolates of Candida glabrata. Six unmatched strains were obtained from an epidemiological survey of candidiasis in immunocompromised hosts that included azole and amphotericin B susceptible and azole resistant clinical isolates. Candida glabrata CBS 138 was used as reference strain. Antifungal susceptibility testing of clinical isolates was evaluated using Clinical and Laboratory Standards Institute (CLSI) methods. Complementary DNA-amplified fragment length polymorphism (cDNA-AFLP) technology, semi-quantitative RT-PCR, and sequencing were employed for identification of potential genes involved in azole resistance. Candida glabrata Candida drug resistance 1 (CgCDR1) and Candida glabrata Candida drug resistance 2 (CgCDR2) genes, which encode for multidrug transporters, were found to be upregulated in azole-resistant isolates (≥2-fold). Fatty acid activator 1 (FAA1) gene, belonging to Acyl-CoA synthetases, showed expression in resistant isolates ≥2-fold that of the susceptible isolates and the reference strain. This study revealed overexpression of the CgCDR1, CgCDR2, and FAA1 genes affecting biological pathways, small hydrophobic compounds transport, and lipid metabolism in the resistant clinical C.glabrata isolates.
Asunto(s)
Antifúngicos/farmacología , Azoles/farmacología , Candida glabrata/genética , Coenzima A Ligasas/metabolismo , Genes MDR , Adulto , Análisis del Polimorfismo de Longitud de Fragmentos Amplificados , Azoles/inmunología , Candida glabrata/efectos de los fármacos , Candida glabrata/aislamiento & purificación , Candidiasis/microbiología , Farmacorresistencia Fúngica/genética , Femenino , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana EdadAsunto(s)
Aspergilosis/tratamiento farmacológico , Aspergilosis/epidemiología , Aspergillus fumigatus , Azoles/uso terapéutico , Farmacorresistencia Fúngica/inmunología , Huésped Inmunocomprometido/inmunología , Antifúngicos/inmunología , Antifúngicos/uso terapéutico , Aspergilosis/inmunología , Azoles/inmunología , Alemania/epidemiología , Humanos , Vigilancia de la Población , Prevalencia , Factores de RiesgoRESUMEN
Slow-reacting substance of anaphylaxis (SRS-A) is an important factor mediating bronchoconstriction in asthma. We developed a guinea pig model for SRS-A mediated bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled WP871, a new anti-allergic drug, on bronchoconstriction. Aerosol WP871 (0.01 and 0.033%) to some extent inhibited the antigen-induced bronchoconstriction in a dose-dependent fashion, but high-dose WP871 (0.1%) inhalation itself produced a non-specific bronchoconstriction. However, aerosol WP871 (0.033%) showed no inhibitory effect on bronchoconstriction caused by direct inhalation of leukotriene C4, a component of SRS-A. These findings indicate that aerosol WP871 does not antagonize SRS-A, but inhibits synthesis and/or release of SRS-A and has some non-specific bronchoconstrictive effect in high concentration.