CinA mediates multidrug tolerance in Mycobacterium tuberculosis

Area of Science:

• Microbiology
• Drug Discovery
• Tuberculosis Research

Background:

• Tuberculosis (TB) treatment is prolonged due to Mycobacterium tuberculosis (Mtb) antibiotic resistance and tolerance.
• Developing new TB chemotherapies is crucial to combat drug-resistant strains and improve patient outcomes.

Purpose of the Study:

• To identify key determinants of Mtb drug tolerance.
• To evaluate the Mtb protein CinA as a potential therapeutic target for shortening TB chemotherapy.

Main Methods:

• Genetic inactivation of the cinA gene in Mtb.
• Assessing the killing kinetics of Mtb ΔcinA with various antibiotics (isoniazid, ethionamide, delamanid, pretomanid).
• Evaluating Mtb ΔcinA efficacy in diverse in vitro and in vivo models, including nutrient starvation, caseum mimetic, macrophages, and chronic mouse infection.
• Investigating the mechanism of CinA-mediated drug tolerance through genetic and drug metabolism studies.

Main Results:

• Genetic inactivation of cinA significantly reduced the fraction of drug-tolerant Mtb persisters.
• Mtb ΔcinA exhibited accelerated killing by isoniazid, ethionamide, delamanid, and pretomanid.
• CinA deletion enhanced Mtb killing under conditions that typically impair antibiotic efficacy and improved in vivo killing by the BPaL regimen.

Conclusions:

• The Mtb protein CinA is a major determinant of antibiotic tolerance.
• Targeting CinA offers a promising strategy to shorten tuberculosis chemotherapy by reducing drug-tolerant persisters.
• CinA likely mediates drug tolerance through the cleavage of NAD-drug adducts.