Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis

Abstract

IQG-607 is a metal complex previously reported as a promising anti-tuberculosis (TB) drug against isoniazid (INH)-resistant strains of Unexpectedly, we found that INH-resistant clinical isolates were resistant to IQG-607. Spontaneous mutants resistant to IQG-607 were subjected to whole-genome sequencing, and all sequenced colonies carried alterations in the gene. The (S315T) mutation was sufficient to confer resistance to IQG-607 in both MIC assays and inside macrophages. Moreover, overexpression of the InhA(S94A) protein caused IQG-607's resistance.

Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates

“…CDCT-16 is an MDR-TB strain that holds mutations in the rpo B (D516V) and kat G (S315T) genes, as well as in the inhA promoter sequence [C(-15)T]. CDCT-27 carries the same mutation in the katG gene, which confers cross-resistance to isoniazid [ 54 ]. As shown in Table 2 , none of these clinical isolates exhibited resistance to compounds 8a , 8c and 8f , with MIC values ranging from 0.8 to 3.1 μM.…”

Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

“…Hence, in the secure environment of the culture medium, the protective role displayed by KatG against oxidative burst would not be required (Manca et al, 1999 ; Brossier et al, 2016 ). Two colonies harbored missense mutations in the katG gene (W91R and H417D), providing further support for KatG activation of IQG-607 (Abbadi et al, 2018 ). The W91R KatG mutant was described at low frequency in clinical isolates (Ramaswamy et al, 2003 ; Vilchèze and Jacobs, 2014 ), while the H417D KatG mutant had not been previously reported.…”

“…To try to shed light on the mechanism of resistance of M. tuberculosis to IQG-607, its inhibitory activity against MDR-TB clinical isolates harboring the KatG(S315T) mutation was evaluated (the description of inhA promoter, katG and rpoB gene mutations of these isolates are described in Table 1 of Abbadi et al, 2018 ). Surprisingly, eight of the nine clinical isolates tested were resistant to both IQG-607 and INH, with MIC values larger than 100 μg/mL (Abbadi et al, 2018 ).…”

“…To try to shed light on the mechanism of resistance of M. tuberculosis to IQG-607, its inhibitory activity against MDR-TB clinical isolates harboring the KatG(S315T) mutation was evaluated (the description of inhA promoter, katG and rpoB gene mutations of these isolates are described in Table 1 of Abbadi et al, 2018 ). Surprisingly, eight of the nine clinical isolates tested were resistant to both IQG-607 and INH, with MIC values larger than 100 μg/mL (Abbadi et al, 2018 ). These results were unexpected and challenged both mechanisms of action previously proposed for this compound, since it suggested an association between the presence of the S315T mutation found in the eight clinical isolates and increased MIC values (>64-fold) for IQG-607, implying that KatG activation is needed for its inhibitory activity.…”

“…Whole-genome and targeted DNA sequencing of six resistant colonies showed that all of them harbored alterations in the katG gene, thereby suggesting that IQG-607 needs to be activated by M. tuberculosis KatG enzyme. Four colonies had single deletions in the gene-coding sequence that led to frameshift mutations (Abbadi et al, 2018 ), a genetic profile that is not common in clinical isolates. These findings were in agreement with previous reports using INH to isolate in vitro spontaneous mutants (Bergval et al, 2009 ; Brossier et al, 2016 ).…”