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Síntesis total quimioenzimática y diversificación estructural de antibióticos macrolidos basados en tilactonas a

Andrew N Lowell¹, Matthew D DeMars¹, Samuel T Slocum¹

¹Life Sciences Institute, ‡Department of Medicinal Chemistry, §Department of Chemistry, and ∥Department of Microbiology & Immunology, University of Michigan , Ann Arbor, Michigan 48109, United States.

Journal of the American Chemical Society

|May 20, 2017

Resumen

Este estudio utiliza policetidas sintasas (PKS) para sintetizar antibióticos macrólidos, logrando la primera síntesis total de las clases de juvenimicina, M-4365 y rosamicina. El enfoque quimioenzimático permitió la construcción escalable de estos productos naturales complejos.

Área de la Ciencia:

La bioquímica
Química orgánica
Biología sintética

Sus antecedentes:

Las poliquetidas sintasas (PKS) son biocatalizadores versátiles para la formación y oxidación de enlaces carbono-carbono.
Los antibióticos macrolides como la tilosina, la juvenimicina, la M-4365 y la rosamicina son productos naturales complejos con un potencial terapéutico significativo.

Objetivo del estudio:

Explorar la funcionalidad de los módulos terminales de la PKS en la biosíntesis de la tilosina para la síntesis quimioenzimática.
Para lograr la primera síntesis total de juvenimicina, M-4365, y las clases de rosamicina de los antibióticos macrólidos.
Desarrollar una ruta sintética escalable para los productos naturales macrólidos a través de la diversificación en etapa tardía.

Principales métodos:

Síntesis quimioenzimática utilizando módulos PKS (JuvEIV y JuvEV) para transformar un intermediario de hexaketida en tilactona.
Elongamiento enzimático in vitro, funcionalización y ciclización de las unidades cetidas.
Diversificación en etapa tardía que incluye la glicosilación in vivo, la oxidación in vitro mediada por el citocromo P450 y la oxidación química.

Principales resultados:

Síntesis exitosa de tilactona utilizando dos módulos terminales de PKS de la vía de la tilosina.
Finalización de la primera síntesis total de juvenimicina, M-4365 y las clases de antibióticos macrólidos rosamicina.
Construcción escalable de productos naturales de macrólidos en 15 pasos lineales (21 en total) con un rendimiento general del 4,6%.

Conclusiones:

Los módulos PKS terminales pueden emplearse eficazmente como biocatalizadores en la síntesis quimioenzimática.
Esta estrategia permite la síntesis total eficiente y escalable de diversas clases de antibióticos macrólidos.
La diversificación en etapa tardía proporciona un enfoque poderoso para generar bibliotecas de productos naturales complejos.

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