• anti-virulence strategies
• mmpS6-mmpL6
• Mycobacterium tuberculosis
• TbD1
• tuberculosis

M. tuberculosis (Mtb) is the causative agent of human tuberculosis, a global health emergency. The emergence of multi-drug-resistant strains makes the development of innovative therapeutic approaches extremely urgent. In this context, the anti-virulence strategies have acquired significant interest. Differently from conventional approaches, targeting bacterial factors essential for viability, these strategies rely on targeting tubercular factors required for replication, thus helping the host immune system in bacterial elimination and reducing the probability of occurrence of antibiotic resistance.
The TbD1/mmpS6-mmpL6 deletion is the genetic hallmark of globally spread Mtb strains in comparison with Mtb TbD1-intact strains restricted to specific geographic areas. Due to the previously demonstrated MmpS6-MmpL6-dependent sensitivity to oxidative stress and hypoxia, MmpS6-MmpL6 proteins represent interesting targets for anti-virulence compounds designed for selectively binding the mmpS6-mmpL6-repressors, and treating Mtb-TbD1-positive-sustained infections. In the first part of the study, the activity of an artificial ligand of a putative mmpS6-mmpL6 repressor on resistance to H2O2 was explored in TbD1-intact and -deleted strains. In the second part, two Mtb strains, mutant for the predicted mmpS6-mmpL6 repressors MTB36_2740023 and MTB36_540006 were constructed and characterized for their mmpL6 transcription profile, as well as for their resistance to oxidative stress.