CinA mediates multidrug tolerance in Mycobacterium tuberculosis.

Nature communications, Volume: 13, Issue: 1
April 22, 2022
Kaj M Kreutzfeldt KM, Robert S Jansen RS, Travis E Hartman TE, Alexandre Gouzy A, Ruojun Wang R, Inna V Krieger IV, Matthew D Zimmerman MD, Martin Gengenbacher M, Jansy P Sarathy JP, Min Xie M, Véronique Dartois V, James C Sacchettini JC, Kyu Y Rhee KY, Dirk Schnappinger D, Sabine Ehrt S

The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.