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Los antibióticos peptidomiméticos se dirigen a la biogénesis de la membrana externa en Pseudomonas aeruginosa
Nityakalyani Srinivas1, Peter Jetter, Bernhard J Ueberbacher
1Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Science (New York, N.Y.)
|February 20, 2010
Resumen
Los nuevos antibióticos peptidomiméticos son prometedores contra las Pseudomonas resistentes a los medicamentos. Dirigidos a la biogénesis de la membrana externa, estos compuestos ofrecen un nuevo mecanismo de acción para el tratamiento de infecciones graves.
Área de la Ciencia:
- Química medicinal Química medicinal es el campo de la química medicinal.
- Microbiología Microbiología.
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- La resistencia a los antibióticos es un desafío crítico para la salud mundial, que requiere nuevos agentes antimicrobianos.
- Los antibióticos existentes son cada vez más ineficaces contra los microorganismos patógenos resistentes.
- Se necesita con urgencia el desarrollo de nuevos medicamentos con mecanismos únicos de acción.
Objetivo del estudio:
- Para sintetizar y optimizar los antibióticos peptidomiméticos basados en protegrina I.
- Para identificar el objetivo celular y el mecanismo de acción de los nuevos peptidomiméticos.
- Para evaluar el potencial terapéutico de estos compuestos contra las bacterias resistentes.
Principales métodos:
- Síntesis peptidomimética y optimización iterativa.
- Análisis de actividad antimicrobiana contra varias cepas bacterianas (Gram-negativas y Gram-positivas).
- Análisis bioquímicos y genéticos para determinar el mecanismo de acción y los objetivos celulares.
- Estudios de eficacia in vivo utilizando un modelo de infección por septicemia en ratones.
Principales resultados:
- Un compuesto peptidomimético de plomo demostró una alta potencia (rango nanomolar) contra las especies de Pseudomonas.
- El compuesto exhibió un mecanismo de acción no membrana-lítico.
- Un homólogo de la proteína beta-barril LptD (Imp / OstA), involucrado en la biogénesis de la membrana externa, fue identificado como el objetivo celular.
- Se observó una actividad antimicrobiana significativa en un modelo de septicemia de ratón.
Conclusiones:
- Los peptidomiméticos dirigidos a la LptD representan una nueva clase prometedora de antibióticos.
- Estos compuestos muestran potencial para el tratamiento de infecciones causadas por Pseudomonas resistentes a los medicamentos.
- Un mayor desarrollo podría conducir a importantes aplicaciones terapéuticas contra patógenos bacterianos difíciles.
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