Tuberculosis (TB) is still a major health issue worldwide. The standard anti-TB chemotherapy is composed of 4 antibiotics that require to be administrated daily over at least 6 months. Within this combination, pyrazinamide (PZA) plays a key role by drastically reducing the duration of the treatment and limiting relapses. However, despite being used clinically for almost 50 years, the molecular mode of action (MoA) of PZA remains poorly characterized with conflicted models reported.
In this project, we aimed at challenging the current views regarding PZA MoA and solve this unique mystery.
By developing innovative CRISPRI approaches and combining it with standard antimicrobial susceptibility testing at various pH and fluorescence-based live recording of Mtb intrabacterial pH, we investigate what are the molecular factors driving PZA’s ability to disrupt Mtb viability and intrabacterial pH homeostasis.