The emergence and spread of drug-resistant
Mycobacterium tuberculosis strains (including MDR, XDR, and TDR) force scientists worldwide to search for new anti-tuberculosis drugs. We have previously reported a number of imidazo[1,2-
b][1,2,4,5]tetrazines – putative inhibitors of mycobacterial eukaryotic-type serine-threonine protein-kinases, active against
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The emergence and spread of drug-resistant
Mycobacterium tuberculosis strains (including MDR, XDR, and TDR) force scientists worldwide to search for new anti-tuberculosis drugs. We have previously reported a number of imidazo[1,2-
b][1,2,4,5]tetrazines – putative inhibitors of mycobacterial eukaryotic-type serine-threonine protein-kinases, active against
M. tuberculosis. Whole genomic sequences of spontaneous drug-resistant
M. smegmatis mutants revealed four genes possibly involved in imidazo[1,2-
b][1,2,4,5]tetrazines resistance; however, the exact mechanism of resistance remain unknown. We used different approaches (construction of targeted mutants, overexpression of the wild-type (
w.t.) and mutant genes, and gene-expression studies) to assess the role of the previously identified mutations. We show that mutations in
MSMEG_1380 gene lead to overexpression of the
mmpS5-mmpL5 operon in
M. smegmatis, thus providing resistance to imidazo[1,2-
b][1,2,4,5]tetrazines by increased efflux through the MmpS5-MmpL5 system, similarly to the mechanisms of resistance described for
M. tuberculosis and
M. abscessus. Mycobacterial MmpS5-MmpL5 transporters should be considered as an MDR-efflux system and they should be taken into account at early stages of anti-tuberculosis drug development.
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