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Las aminas secundarias simples inhiben el crecimiento de bacterias gramnegativas a través de la unión altamente

Vadim Baidin¹, Tristan W Owens¹, Michael B Lazarus²

¹Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.

Journal of the American Chemical Society

|January 7, 2021

Resumen

Un nuevo antibiótico de aminas secundarias ataca selectivamente a las bacterias gramnegativas inhibiendo la enzima PheRS. Este descubrimiento ofrece un andamiaje prometedor para el desarrollo de nuevos tratamientos contra las infecciones Gram-negativas resistentes a los medicamentos.

Área de la Ciencia:

Química medicinal
Microbiología
Biología estructural

Sus antecedentes:

Las infecciones gramnegativas resistentes a los medicamentos representan una amenaza significativa para la salud mundial, lo que requiere el descubrimiento de nuevos antibióticos.
Las opciones de tratamiento existentes son limitadas y el desarrollo de nuevos agentes antimicrobianos contra estos patógenos es un desafío.

Objetivo del estudio:

Identificar y caracterizar nuevos compuestos con actividad contra las bacterias gramnegativas resistentes a los medicamentos.
Aclarar el mecanismo de acción y la selectividad de un nuevo andamio antibiótico identificado.

Principales métodos:

Se utilizó una prueba basada en células para identificar inhibidores del crecimiento de bacterias Gram negativas.
Se mapearon las mutaciones de resistencia para identificar la enzima diana, seguidas de ensayos bioquímicos.
Se determinaron las estructuras cristalinas de la enzima diana compleja con el inhibidor.
El análisis bioinformático y la mutagénesis se utilizaron para comprender la selectividad.

Principales resultados:

Se identificó una amina secundaria simple que inhibe el crecimiento de Escherichia coli y Acinetobacter baumannii, pero no de Bacillus subtilis.
Las mutaciones de resistencia asignadas a la aminoacil-tRNA sintetasa PheRS, lo que confirma que es el objetivo.
Los estudios estructurales y bioquímicos revelaron que el compuesto inhibe selectivamente el PheRS Gram-negativo al inducir una bolsa hidrofóbica específica.
El compuesto demostró actividad contra patógenos gramnegativos de tipo salvaje y no fue citotóxico para las células de mamíferos.

Conclusiones:

Un nuevo andamio de aminas secundarias se dirige selectivamente a los PheRS gramnegativos, ofreciendo un punto de partida prometedor para el desarrollo de nuevos antibióticos.
La selectividad del compuesto se basa en su capacidad para inducir un bolsillo hidrofóbico único en PheRS Gram-negativo.
Este andamio tiene potencial para la terapia antibiótica combinada contra las infecciones Gram negativas desafiantes.

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