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American Society for Microbiology, Antimicrobial Agents and Chemotherapy, 1(56), p. 324-331, 2012

DOI: 10.1128/aac.05270-11

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MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212

Journal article published in 2011 by Ioerger Tr, Valentina La Rosa, Giovanna Poce, Julio Ortiz Canseco, J. Ortiz Canseco, Silvia Buroni, Pasca Mr, Maria Rosalia Pasca, Mariangela Biava, Ravikiran M. Raju, Raju Rm, Poretta Gc, Giulio Cesare Porretta, Salvatore Alfonso, S. Alfons and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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 ( m ycobacterial m embrane p rotein, l arge) 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.