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La síntesis de ácidos grasos tipo II no es un objetivo antibiótico adecuado para patógenos Gram-positivos
Sophie Brinster1, Gilles Lamberet, Bart Staels
1Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Nature
|March 6, 2009
Resumen
El desarrollo de antibióticos dirigidos a la vía de síntesis de ácidos grasos II (FASII) es defectuoso. Los ácidos grasos exógenos, como los del suero humano, permiten a las bacterias eludir la inhibición de FASII, lo que hace que estos medicamentos sean ineficaces contra las infecciones Gram-positivas.
Área de la Ciencia:
- Microbiología Microbiología.
- Descubrimiento de Drogas Descubrimiento de Drogas
- La bioquímica es la bioquímica.
Sus antecedentes:
- La vía de síntesis de ácidos grasos tipo II (FASII) se considera esencial para la supervivencia bacteriana.
- Los fármacos antimicrobianos dirigidos a FASII han demostrado ser prometedores contra las bacterias multirresistentes Gram-positivas.
Objetivo del estudio:
- Investigar la eficacia fundamental de la orientación de la vía FASII para el desarrollo de antibióticos.
- Para determinar si los ácidos grasos exógenos pueden superar la inhibición de la vía FASII en patógenos Gram-positivos.
Principales métodos:
- Experimentos in vitro e in vivo con patógenos bacterianos Gram-positivos (Streptococcus, Enterococcus, Staphylococcus) en los que se han utilizado bacterias de las especies de Streptococcus y Staphylococcus.
- Evaluación del crecimiento bacteriano y la expresión génica FASII en presencia de ácidos grasos exógenos y suero humano.
- Generación y análisis de mutantes de deleción de genes objetivo FASII en Streptococcus agalactiae.
Principales resultados:
- Los ácidos grasos exógenos, fácilmente disponibles en el suero humano, evaden efectivamente la inhibición de la vía FASII por los medicamentos antimicrobianos.
- Los principales patógenos Gram-positivos superan la inhibición FASII inducida por fármacos cuando se les suministran ácidos grasos exógenos.
- Se descubrió que las enzimas de la vía FASII eran prescindibles in vivo durante la infección por Streptococcus agalactiae, incluso con la deleción de genes.
Conclusiones:
- La estrategia de desarrollo de antibióticos dirigidos a la vía FASII es fundamentalmente defectuosa debido a los mecanismos de derivación.
- El suero humano actúa como una fuente significativa de ácidos grasos, lo que compromete la eficacia del fármaco dirigido a FASII.
- Los antimicrobianos basados en FASII pueden no ser efectivos para tratar la sepsis causada por patógenos Gram-positivos.
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