CinA mediates multidrug tolerance in Mycobacterium tuberculosis. Academic Article uri icon

abstract

  • 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 cinA 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.

published proceedings

  • Nat Commun

altmetric score

  • 71.75

author list (cited authors)

  • Kreutzfeldt, K. M., Jansen, R. S., Hartman, T. E., Gouzy, A., Wang, R., Krieger, I. V., ... Ehrt, S.

citation count

  • 13

complete list of authors

  • Kreutzfeldt, Kaj M||Jansen, Robert S||Hartman, Travis E||Gouzy, Alexandre||Wang, Ruojun||Krieger, Inna V||Zimmerman, Matthew D||Gengenbacher, Martin||Sarathy, Jansy P||Xie, Min||Dartois, Véronique||Sacchettini, James C||Rhee, Kyu Y||Schnappinger, Dirk||Ehrt, Sabine

publication date

  • January 2022