Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5–MmpL5 efflux system

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 89; no. 1; pp. 84 - 90
• Main Authors: Milano, Anna, Pasca, Maria Rosalia, Provvedi, Roberta, Lucarelli, Anna Paola, Manina, Giulia, Luisa de Jesus Lopes Ribeiro, Ana, Manganelli, Riccardo, Riccardi, Giovanna
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.01.2009
• Subjects: Antifungal Agents - metabolism; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Azole resistance; Azoles - metabolism; Azoles - pharmacology; Azoles - therapeutic use; Base Sequence; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cell Wall - metabolism; Drug Resistance, Multiple, Bacterial - genetics; Econazole - metabolism; Econazole - pharmacology; Econazole - therapeutic use; Efflux pumps; Gene Expression; Gene Expression Profiling - methods; Genes, Bacterial; Infectious Disease; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Mycobacterium bovis; Mycobacterium bovis - genetics; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - metabolism; Oligonucleotide Array Sequence Analysis; Pulmonary/Respiratory; Reverse Transcriptase Polymerase Chain Reaction - methods; RND transporters; Tuberculosis - drug therapy; Tuberculosis - microbiology; Uncoupling Agents - pharmacology; Efflux pumps; RND transporters; Mycobacterium tuberculosis; Azole resistance
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2008.08.003

Summary Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis . Moreover, the recent isolation of M. tuberculosis strains resistant to both first- and second-line antitubercular drugs (XDR–TB) threatens to make the treatment of this disease extremely difficult and becoming a threat to public health worldwide. Recently, it has been shown that azoles are potent inhibitors of mycobacterial cell growth and have antitubercular activity in mice, thus favoring the hypothesis that these drugs may constitute a novel strategy against tuberculosis disease. To investigate the mechanisms of resistance to azoles in mycobacteria, we isolated and characterized several spontaneous azoles resistant mutants from M. tuberculosis and Mycobacterium bovis BCG. All the analyzed resistant mutants exhibited both increased econazole efflux and increased transcription of mmpS5 – mmpL5 genes, encoding a hypothetical efflux system belonging to the resistance–nodulation–division (RND) family of transporters. We found that the up-regulation of mmpS5 – mmpL5 genes was linked to mutations either in the Rv0678 gene, hypothesized to be involved in the transcriptional regulation of this efflux system, or in its putative promoter/operator region.