CinA mediates multidrug tolerance in Mycobacterium tuberculosis

Kaj M. Kreutzfeldt, Robert S. Jansen, Travis E. Hartman, Alexandre Gouzy, Ruojun Wang, Inna V. Krieger, Matthew D. Zimmerman, Martin Gengenbacher, Jansy P. Sarathy, Min Xie, Véronique Dartois, James C. Sacchettini, Kyu Y. Rhee, Dirk Schnappinger () and Sabine Ehrt ()
Additional contact information
Kaj M. Kreutzfeldt: Weill Cornell Medical College
Robert S. Jansen: Weill Cornell Medical College
Travis E. Hartman: Weill Cornell Medical College
Alexandre Gouzy: Weill Cornell Medical College
Ruojun Wang: Weill Cornell Medical College
Inna V. Krieger: Texas A&M University
Matthew D. Zimmerman: Hackensack Meridian Health
Martin Gengenbacher: Hackensack Meridian Health
Jansy P. Sarathy: Hackensack Meridian Health
Min Xie: Hackensack Meridian Health
Véronique Dartois: Hackensack Meridian Health
James C. Sacchettini: Texas A&M University
Kyu Y. Rhee: Weill Cornell Medical College
Dirk Schnappinger: Weill Cornell Medical College
Sabine Ehrt: Weill Cornell Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29832-1

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DOI: 10.1038/s41467-022-29832-1

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