Publication: Papel del estrés oxidativo en el mecanismo de acción de la anfotericina B y evaluación de la virulencia de hongos patógenos y de la eficacia de antifúngicos en Galleria mellonella
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2015-03-04
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Universidad Complutense de Madrid
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Abstract
La incidencia de las infecciones fúngicas ha aumentado en los últimos años como cosecuencia del incremento en el numero pacientes inmunosuprimidos. Aunque especies de los géneros Candida, Aspergillus y Cryptococcus son las más frecuntes, es notoria la emergencia de nuevas especies con baja sensibilidad o resistencia a los principales antifúngicos. El tratamiento de las infecciones fungicas se basa principalmente en fármacos de la familia de los polienos (anfotericina B) de los azoles (fluconazol, vorivonazol, itraconazol y posaconazol) y de las equinocandinas (caspofungina, anidulafungina y micafungina). A pesar de ello, el número de antifúngicos es limitado para afrontar el reto terapeutico que imopenen estas infecciones. Lo anterior indica que existe una necesidad de desarrollar nuevas moleculas, o bien, modificar las ya existentes. El últimao caso, implica el conocimiento de mecanismos de acción y de resistencia de los fármacos en uso. Ademas es importante disponer de un modelo animal para evaluar la correlación de la susceptibilidad in vitro con la eficacia in vivo. La anfotercina B es un antifúngico con amplio especto de acción y unos de los más utilizados en la clinica y apesar de llevar más de 50 años en el mercado, no se conoce con precisión su mecanismo de acción. Inicialmente, el efecto fungicida se atribuyó a la capacidad para formar poros en la membrana tras la unión al ergosterol. Sin embargotambién se ha sugerido la participación de otros mecanismos como dependiente de la simple unión de la anfotericina B al ergosterol o la inducción de estrés oxidativo. La importancia el último mecanismo en la acción fungicida de la anfotericina B ha sido poco estudiada...
The incidence of opportunistic fungal infections has increased significantly in recent decades, and nowadays, it represents a significant human health problem. This rise has mainly been caused by an increase in immunocompromised patients, but there are also other factors that contribute to the occurrence of new cases of fungal infections, such as the use of broad-spectrum antibiotics, prolonged hospitalization, parenteral nutrition, advanced age, and diabetes. Among fungal pathogens, the species of Candida, Aspergillus and Cryptococcus are the most frequent in human infections, but other emerging fungi are increasing and some of them are resistant or have low sensitivity to antifungal activity. Most invasive and disseminated infections are caused by Candida species (70- 90%), and mortality can be very high, as is the case of candidaemia (around 40-50%) depending on patient condition and the species involved. Candida albicans is the most virulent species and the most frequently isolated. It is also the most important within the genus in terms of clinic issues. On the other hand, non-albicans species are normally more resistant to antifungal agents than C. albicans, and in recent years, their incidence has significantly increased, in such a way that they now account for approximately 50% of all episodes of candidaemia. These species are mainly C. glabrata, C. parapsilosis, C. tropicalis and C. krusei. Candida species and antifungal susceptibility vary according to geographical region. Other clinically important agents are Cryptococcus spp. Cryptococcus neoformans and C. gattii are the most noteworthy species. The former mainly affects inmunocompromised, the latter affects healthy persons. The incidence of infections caused by filamentous fungi is lower than that of those caused by yeast infection, but mortality is higher. The most important genus in this fungal group is Aspergillus, with A. fumigatus being the most relevant from a clinical point of view; other species, such as A. terreus, A. flavus, A. nidulans, A, lentulus and A. niger, have shown an increased incidence among susceptible patients...
The incidence of opportunistic fungal infections has increased significantly in recent decades, and nowadays, it represents a significant human health problem. This rise has mainly been caused by an increase in immunocompromised patients, but there are also other factors that contribute to the occurrence of new cases of fungal infections, such as the use of broad-spectrum antibiotics, prolonged hospitalization, parenteral nutrition, advanced age, and diabetes. Among fungal pathogens, the species of Candida, Aspergillus and Cryptococcus are the most frequent in human infections, but other emerging fungi are increasing and some of them are resistant or have low sensitivity to antifungal activity. Most invasive and disseminated infections are caused by Candida species (70- 90%), and mortality can be very high, as is the case of candidaemia (around 40-50%) depending on patient condition and the species involved. Candida albicans is the most virulent species and the most frequently isolated. It is also the most important within the genus in terms of clinic issues. On the other hand, non-albicans species are normally more resistant to antifungal agents than C. albicans, and in recent years, their incidence has significantly increased, in such a way that they now account for approximately 50% of all episodes of candidaemia. These species are mainly C. glabrata, C. parapsilosis, C. tropicalis and C. krusei. Candida species and antifungal susceptibility vary according to geographical region. Other clinically important agents are Cryptococcus spp. Cryptococcus neoformans and C. gattii are the most noteworthy species. The former mainly affects inmunocompromised, the latter affects healthy persons. The incidence of infections caused by filamentous fungi is lower than that of those caused by yeast infection, but mortality is higher. The most important genus in this fungal group is Aspergillus, with A. fumigatus being the most relevant from a clinical point of view; other species, such as A. terreus, A. flavus, A. nidulans, A, lentulus and A. niger, have shown an increased incidence among susceptible patients...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Parasitología, leída el 19/09/2014