Comparative study of enzymatic activities of new KatG mutants from low- and high-level isoniazid-resistant clinical isolates of Mycobacterium tuberculosisReportar como inadecuado




Comparative study of enzymatic activities of new KatG mutants from low- and high-level isoniazid-resistant clinical isolates of Mycobacterium tuberculosis - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 CIMI - Centre d-Immunologie et de Maladies Infectieuses 2 Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux CHU Pitié-Salpêtrière 3 UPD7 - Université Paris Diderot - Paris 7 4 Microbiologie structurale

Abstract : Resistance to isoniazid INH-R in Mycobacterium tuberculosis is mainly due to mutations at position 315 S315T of the catalase-peroxidase KatG. We identified 16 mutations including 13 biochemically uncharacterized mutations in KatG from INH-R clinical isolates of M. tuberculosis showing mutations other than S315T. The KatG enzymatic activities catalase, peroxidase, free radical production and isonicotinoyl-NAD formation of wild-type KatG and the 16 mutants were determined and correlated to their spatial location in a KatG model structure. Of all mutations studied, H270R, which conferred a high level of INH-R and results in the disruption of a coordination bond with the heme, caused complete loss of all enzymatic KatG activities. The mutants generally associated with a very high level of INH-R were all characterized by a drastic reduction in catalase activity and a marked decrease in INH activation activities. One mutant, A162E, displayed a behavior similar to S315T, i.e. a moderate decrease in catalase activity and a drastic decrease in the formation of the radical form of INH. Finally, the mutants associated with a low level of INH-R showed a moderate reduction in the four catalytic activities, likely stemming from an overall alteration of the folding and-or stability of the KatG protein.

Keywords : Tuberculosis Catalase-peroxidase Enzymatic activities KatG Resistance Isoniazid





Autor: Florence Brossier - Marlène Boudinet - Vincent Jarlier - Stéphanie Petrella - Wladimir Sougakoff -

Fuente: https://hal.archives-ouvertes.fr/



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