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Aislamiento, estructura y actividad antibacteriana de la filipimicina, un péptido tiazolílico descubierto en

Chaowei Zhang¹, James Occi, Prakash Masurekar

¹Merck Research Laboratories, Rahway, New Jersey 07065, USA.

Journal of the American Chemical Society

|August 14, 2008

Resumen

Los investigadores descubrieron la filipimicina, un nuevo antibiótico glucósido de péptido tiazolílico, eficaz contra las bacterias resistentes a los medicamentos como el MRSA. Este nuevo antibiótico se dirige a la síntesis de proteínas bacterianas y se muestra prometedor in vivo, ofreciendo un nuevo arma potencial contra la resistencia a los antibióticos.

Área de la Ciencia:

Microbiología y Química de Productos Naturales.
Descubrimiento y Desarrollo de Drogas.

Sus antecedentes:

La resistencia a los antibióticos, especialmente a las cepas multirresistentes, es una preocupación crítica para la salud mundial.
Se necesitan con urgencia nuevos antibióticos con nuevos mecanismos de acción.
Los péptidos tiazolil son potentes antibióticos, pero a menudo tienen pobres propiedades farmacéuticas.

Objetivo del estudio:

Descubrir nuevos péptidos tiazolilo con propiedades potencialmente mejoradas.
Para identificar nuevos antibióticos eficaces contra las cepas bacterianas resistentes.

Principales métodos:

Desarrollo de un ensayo específico utilizando cepas de Staphylococcus aureus.
Fraccionamiento guiado por bioensayo para el aislamiento de compuestos.
Elucidación de la estructura mediante técnicas espectroscópicas avanzadas (2D NMR, HRESIFT-MS/MS).
Pruebas de actividad antibacteriana in vitro e in vivo.
Estudios sobre el mecanismo de acción, incluidos estudios de inhibición de la síntesis de proteínas y estudios de acoplamiento.

Principales resultados:

Descubrimiento y aislamiento de la filipimicina, un nuevo glucósido de péptido tiazolílico, y su producto de degradación.
Ambos compuestos mostraron una potente actividad contra las bacterias Gram-positivas, incluido el Staphylococcus aureus resistente a la meticilina (MRSA), con MIC de 0,015 a 1 microg / ml.
La filipimicina demostró una potencia superior en comparación con su producto de degradación.
Se observó una inhibición selectiva de la síntesis de proteínas, lo que indica una orientación ribosómica.
La filipimicina mostró eficacia en un modelo de ratón de infección por S. aureus (ED50 = 8,4 mg/kg).
Los estudios de acoplamiento proporcionaron información sobre la interacción con el ribosoma y la proteína L11, explicando la actividad diferencial contra las cepas resistentes.

Conclusiones:

La filipimicina es un nuevo antibiótico de péptido tiazolílico prometedor con una potente actividad contra las bacterias Gram-positivas, incluido el MRSA.
Su novedoso mecanismo dirigido a la síntesis de proteínas y su eficacia demostrada in vivo merecen una mayor investigación.
Comprender su interacción con el ribosoma y los mecanismos de resistencia puede guiar el desarrollo futuro de antibióticos.

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