CinA mediates multidrug tolerance in Mycobacterium tuberculosis.
Kaj M KreutzfeldtRobert S JansenTravis E HartmanAlexandre GouzyRuojun WangInna V KriegerMatthew D ZimmermanMartin GengenbacherJansy P SarathyMin XieVeronique Anne DartoisJames C SacchettiniKyu Y RheeDirk SchnappingerSabine EhrtPublished in: Nature communications (2022)
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.
Keyphrases
- mycobacterium tuberculosis
- drug resistant
- pulmonary tuberculosis
- multidrug resistant
- acinetobacter baumannii
- adverse drug
- drug induced
- emergency department
- gene expression
- staphylococcus aureus
- squamous cell carcinoma
- hepatitis c virus
- risk assessment
- protein protein
- case control
- electronic health record
- human health