Skip to Main content Skip to Navigation
Journal articles

Dissecting erm (41)-Mediated Macrolide-Inducible Resistance in Mycobacterium abscessus

Abstract : Macrolides are the cornerstone of Mycobacterium abscessus multidrug therapy, despite that most patients respond poorly to this class of antibiotics due to the inducible resistance phenotype that occurs during drug treatment. This mechanism is driven by the macrolide-inducible ribosomal methylase encoded by erm(41), whose expression is activated by the transcriptional regulator WhiB7. However, it has been debated whether clarithromycin and azithromycin differ in the extent to which they induce erm(41)-mediated macrolide resistance. Herein, we show that macrolide resistance is induced more rapidly in various M. abscessus isolates upon exposure to azithromycin than to clarithromycin, based on MIC determination. Macrolide-induced expression of erm(41) was assessed in vivo using a strain carrying tdTomato placed under the control of the erm(41) promoter. Visualization of fluorescent bacilli in infected zebrafish demonstrates that azithromycin and clarithromycin activate erm(41) expression in vivo. That azithromycin induces a more rapid expression of erm(41) was confirmed by measuring the ␤-galactosidase activity of a reporter strain in which lacZ was placed under the control of the erm(41) promoter. Shortening the promoter region in the lacZ reporter plasmid identified DNA elements involved in the regulation of erm(41) expression, particularly an AT-rich motif sharing partial conservation with the WhiB7-binding site. Mutation of this motif abrogated the macrolide-induced and WhiB7-dependent expression of erm(41). This study provides new mechanistic information on the adaptive response to macrolide treatment in M. abscessus.
Document type :
Journal articles
Complete list of metadatas

Cited literature [51 references]  Display  Hide  Download

https://www.hal.inserm.fr/inserm-02868861
Contributor : Laurent Kremer <>
Submitted on : Monday, June 15, 2020 - 4:27:08 PM
Last modification on : Tuesday, June 16, 2020 - 3:45:18 AM

File

 Restricted access
To satisfy the distribution rights of the publisher, the document is embargoed until : jamais

Please log in to resquest access to the document

Identifiers

Collections

Citation

Matthias Richard, Ana Victoria Gutiérrez, Laurent Kremer. Dissecting erm (41)-Mediated Macrolide-Inducible Resistance in Mycobacterium abscessus. Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2020, 64 (2), pp.e01879-19. ⟨10.1128/AAC.01879-19⟩. ⟨inserm-02868861⟩

Share

Metrics

Record views

21