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La resistencia a los fármacos antimicóticos provocada a través de epimutaciones dependientes del ARNi
Silvia Calo1, Cecelia Shertz-Wall1, Soo Chan Lee1
1Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature
|August 1, 2014
Resumen
Mucor circinelloides desarrolla resistencia a los fármacos antifúngicos a través de mutaciones mendelianas estables o silenciamiento epigenético inestable mediado por interferencia de ARN epigenético (RNAi) del gen fkbA.
Área de la Ciencia:
- La micología de la micología.
- Biología Molecular Biología Molecular
- Genética La genética.
Sus antecedentes:
- Los microorganismos desarrollan diversos mecanismos para la adaptación.
- La resistencia a los medicamentos antimicóticos es una preocupación creciente para la salud pública.
- Los mecanismos de adaptación del patógeno fúngico humano Mucor circinelloides no se comprenden completamente.
Objetivo del estudio:
- Para investigar los mecanismos de resistencia espontánea al fármaco antifúngico FK506 (tacrolimus) en Mucor circinelloides.
- Aclarar el papel de las mutaciones mendelianas y las vías epigenéticas en la resistencia a los medicamentos.
- Para descubrir nuevos mecanismos de epimutación basados en la interferencia de ARN (ARNi).
Principales métodos:
- Análisis genético de mutaciones en los genes fkbA, cnbR y cnaA.
- Evaluación de la resistencia a FK506 y el crecimiento de la hifa.
- Análisis de la vía de la interferencia del ARN (RNAi).
- Detección de ARN pequeños fkbA y generación de ARN antisentido.
Principales resultados:
- Se identificaron dos mecanismos distintos de resistencia a FK506: mutaciones mendelianas estables y silenciamiento epigenético inestable mediado por ARNi de fkbA.
- El silenciamiento mediado por ARNi conduce a epimutantes resistentes a los fármacos que vuelven fácilmente al fenotipo sensible.
- El silenciamiento implica la generación de desencadenantes de ARN de doble cadena y requiere la vía RNAi.
- Los epimutantes resistentes a FK506 están asociados con abundantes ARN pequeños de fkbA.
Conclusiones:
- Mucor circinelloides emplea un nuevo mecanismo de epimutación epigenético basado en ARNi para la plasticidad fenotípica y la resistencia a los medicamentos.
- Este mecanismo proporciona una estrategia de adaptación rápida, aunque inestable.
- Los hallazgos tienen implicaciones para la comprensión de la resistencia a los fármacos antimicrobianos y la regulación del ARNi en los eucariotas.
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