MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. - Archive ouverte HAL Access content directly
Journal Articles Antimicrobial Agents and Chemotherapy Year : 2012

MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212.

(1) , (2, 3) , (1) , (1) , (1) , (3) , (2) , (3) , (3) , (3) , (3) , (2) , (4) , (5) , (6) , (7) , (8) , (2) , (1)
1
2
3
4
5
6
7
8

Abstract

The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and Mycobacterium tuberculosis residing within macrophages as well as against Mycobacterium avium and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the mmpL3 gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (mycobacterial membrane protein, large) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide m-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [(14)C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.
Fichier principal
Vignette du fichier
LaRosaetal2012.pdf (810.84 Ko) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Loading...

Dates and versions

pasteur-00968568 , version 1 (01-04-2014)

Identifiers

Cite

Valentina La Rosa, Giovanna Poce, Julio Ortiz Canseco, Silvia Buroni, Maria Rosalia Pasca, et al.. MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212.. Antimicrobial Agents and Chemotherapy, 2012, 56 (1), pp.324-31. ⟨10.1128/AAC.05270-11⟩. ⟨pasteur-00968568⟩

Collections

RIIP RIIP_FCB
72 View
441 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More