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Se requiere un patrón alternativo de estereoquímica en el macrociclo de la nonactina para la actividad antibacteriana
Brian R Kusche1, Adrienne E Smith, Michele A McGuirl
1Department of Chemistry and Biochemistry, University of Montana, 32 Campus Drive, Missoula, Montana 59812-1656, USA.
Journal of the American Chemical Society
|November 12, 2009
Resumen
La estereoquímica natural de la nonactina, un ionóforo antibiótico, es esencial para su actividad antibacteriana y su capacidad para transportar iones de potasio. Ambos enantiómeros del ácido nonactico son necesarios para la función de la nonactina.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Microbiología Microbiología.
- Biología Química Biología química.
Sus antecedentes:
- Nonactin es un antibiótico policetídeo y un ionóforo selectivo de potasio producido por Streptomyces griseus.
- Posee simetría S4 y es aciral, siendo un tetraéster cíclico de dos monómeros de ácido (+) -nonactico y dos de ácido (-) -nonactico.
- La estereoquímica natural de la nonactina es crucial para su actividad biológica, pero el papel preciso de su composición enantiomérica no se ha aclarado completamente.
Objetivo del estudio:
- Investigar la necesidad de los enantiómeros (+) y (-) del ácido nonactico para las propiedades ionóforas y antibacterianas de la nonactina.
- Para comparar las afinidades de unión y las capacidades de transporte de la nonactina natural con sus diastereoisómeros compuestos de un solo enantiómero de ácido nonactico.
Principales métodos:
- Síntesis de dos diastereoisómeros no naturales: toda la no-actina y toda la no-actina.
- Determinación de la actividad antibacteriana contra los organismos gram-positivos.
- Calorimetría de titulación isotérmica para cuantificar la termodinámica de enlace (K ((a), DeltaG, DeltaH, DeltaS) con K ((+), Na ((+) y NH ((4) ((+).
- Prueba de partición de picrato para evaluar el transporte de iones a través de disolventes orgánicos.
- Modelado computacional para analizar las interacciones estéricas dentro de los complejos iónico-ligando.
Principales resultados:
- Los diastereoisómeros no naturales fueron 500 veces menos activos contra las bacterias gram-positivas en comparación con las nonactinas naturales.
- La nonactina natural exhibió una afinidad de unión 880 veces mayor para K (((+) que todas las ((-) -nonactinas.
- La nonactina no logró dividir los iones K (((+) en disolventes orgánicos, a diferencia de la nonactina.
- El modelado indicó un obstáculo estérico en el complejo all-(-) -nonactina-K(+), evitando la unión fuerte.
Conclusiones:
- La presencia de ambos enantiómeros (+) y (-) del ácido nonactico es indispensable para la formación de la nonactina biológicamente activa.
- La estereoquímica específica de la nonactina dicta su eficacia como ionóforo de potasio y sus propiedades antibacterianas.
- Comprender los requisitos estereoquímicos proporciona información sobre el mecanismo del transporte de iones y la acción de los antibióticos.
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