Deciphering Determinants in Ribosomal Methyltransferases That Confer Antimicrobial Resistance.
J Am Chem Soc
; 141(4): 1425-1429, 2019 01 30.
Article
en En
| MEDLINE
| ID: mdl-30624914
Post-translational methylation of rRNA at select positions is a prevalent resistance mechanism adopted by pathogens. In this work, KsgA, a housekeeping ribosomal methyltransferase (rMtase) involved in ribosome biogenesis, was exploited as a model system to delineate the specific targeting determinants that impart substrate specificity to rMtases. With a combination of evolutionary and structure-guided approaches, a set of chimeras were created that altered the targeting specificity of KsgA such that it acted similarly to erythromycin-resistant methyltransferases (Erms), rMtases found in multidrug-resistant pathogens. The results revealed that specific loop embellishments on the basic Rossmann fold are key determinants in the selection of the cognate RNA. Moreover, in vivo studies confirmed that chimeric constructs are competent in imparting macrolide resistance. This work explores the factors that govern the emergence of resistance and paves the way for the design of specific inhibitors useful in reversing antibiotic resistance.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ribosomas
/
Farmacorresistencia Bacteriana
/
Metiltransferasas
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Am Chem Soc
Año:
2019
Tipo del documento:
Article
País de afiliación:
India
Pais de publicación:
Estados Unidos