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Ingeniería de la gama de huéspedes de los fagos y supresión de la resistencia bacteriana a través de la mutagenesis

Kevin Yehl¹, Sébastien Lemire¹, Andrew C Yang²

¹Synthetic Biology Group, MIT Synthetic Biology Center, The Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Research Laboratory of Electronics, MIT, Cambridge, MA 02139, USA.

|October 5, 2019

Resumen

Las terapias con bacteriófagos son prometedoras contra la resistencia a los antibióticos. La ingeniería de las fibras de la cola de los fagos creó "fagógenos" que previenen la resistencia bacteriana y suprimen el crecimiento in vitro e in vivo.

Área de la Ciencia:

Microbiología
Biología molecular
Biotecnología

Sus antecedentes:

La resistencia a los antibióticos es una amenaza creciente para la salud mundial, que requiere nuevas estrategias terapéuticas.
La terapia con bacteriófagos (fagos) es una alternativa prometedora, pero la resistencia bacteriana a los fagos sigue siendo un desafío.
Los componentes de los fagos de ingeniería pueden superar o retrasar el desarrollo de la resistencia bacteriana.

Objetivo del estudio:

Diseñar las fibras de la cola de los bacteriófagos para alterar el rango del huésped y superar la resistencia bacteriana.
Desarrollar un método de alto rendimiento para generar variantes de fagos diversas y funcionales.
Evaluar la eficacia de los fagos modificados in vitro e in vivo.

Principales métodos:

Regiones determinantes de la gama de huéspedes (HRDR) identificadas en la proteína de la fibra de la cola del fago T3 a través de la evolución natural y el modelado estructural.
Mutagénesis dirigida por el sitio empleada para la ingeniería genética de HRDR, creando "fagógenos" sintéticos.
Se evaluó la gama de huéspedes fagógenos, la supresión del crecimiento bacteriano, la prevención de la resistencia in vitro y la eficacia in vivo en un modelo murino.

Principales resultados:

Las mutaciones en los HRDR alteraron con éxito los rangos de huéspedes fagos.
Los fagobodies diseñados demostraron la supresión a largo plazo del crecimiento bacteriano in vitro al prevenir la resistencia.
Los fagobodies fueron funcionales in vivo, mostrando eficacia en un modelo de infección murina.

Conclusiones:

La ingeniería genética de las HRDR de fibra de cola de fagos es una estrategia viable para crear agentes antimicrobianos potentes.
Este enfoque produce "fagógenos" que pueden retrasar o prevenir el desarrollo de la resistencia bacteriana.
La metodología tiene potencial para desarrollar antimicrobianos de próxima generación y otras aplicaciones de andamio viral.

Palabras clave:

anticuerpo Antimicrobianos y sus derivados bacteriófago La evolución rango de anfitriones el fago la resistencia Biología sintética fibra de la cola el virus

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