Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system.
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.
Milano
Anna
A
Department of Genetics and Microbiology, University of Pavia, Italy.
Pasca
Maria Rosalia
MR
Provvedi
Roberta
R
Lucarelli
Anna Paola
AP
Manina
Giulia
G
Ribeiro
Ana Luisa de Jesus Lopes
AL
Manganelli
Riccardo
R
Riccardi
Giovanna
G
D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001393:Azoles / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002473:Cell Wall / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D004464:Econazole / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D005798:Genes, Bacterial; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009163:Mycobacterium bovis / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology*; D014475:Uncoupling Agents / Q000494:pharmacology
D000935:Antifungal Agents; D001393:Azoles; D026901:Membrane Transport Proteins; D014475:Uncoupling Agents; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D004464:Econazole