Back to Search
Start Over
KatG as Counterselection Marker for Nontuberculous Mycobacteria
- Source :
- Antimicrob Agents Chemother
- Publication Year :
- 2020
- Publisher :
- American Society for Microbiology, 2020.
-
Abstract
- Isoniazid (INH) is a cornerstone of antitubercular therapy. Mycobacterium tuberculosis complex bacteria are the only mycobacteria sensitive to clinically relevant concentrations of INH. All other mycobacteria, including M. marinum and M. avium subsp. paratuberculosis are resistant. INH requires activation by bacterial KatG to inhibit mycobacterial growth. We tested the role of the differences between M. tuberculosis KatG and that of other mycobacteria in INH sensitivity. We cloned the M. bovis katG gene into M. marinum and M. avium subsp. paratuberculosis and measured the MIC of INH. We recombinantly expressed KatG of these mycobacteria and tested in vitro binding to, and activation of, INH. Introduction of katG from M. bovis into M. marinum and M. avium subsp. paratuberculosis rendered them 20 to 30 times more sensitive to INH. Analysis of different katG sequences across the genus found KatG evolution diverged from RNA polymerase-defined mycobacterial evolution. Biophysical and biochemical tests of M. bovis and nontuberculous mycobacteria (NTM) KatG proteins showed lower affinity to INH and substantially lower enzymatic capacity for the conversion of INH into the active form in NTM. The KatG proteins of M. marinum and M. avium subsp. paratuberculosis are substantially less effective in INH activation than that of M. tuberculosis, explaining the relative INH insensitivity of these microbes. These data indicate that the M. tuberculosis complex KatG is divergent from the KatG of NTM, with a reciprocal relationship between resistance to host defenses and INH resistance. Studies of bacteria where KatG is functionally active but does not activate INH may aid in understanding M. tuberculosis INH-resistance mechanisms, and suggest paths to overcome them.
- Subjects :
- Antitubercular Agents
Mycobacterium Infections, Nontuberculous
610 Medicine & health
Mycobacterium abscessus
Microbiology
Mycobacterium
Heme-Binding Proteins
Bacterial Proteins
Mechanisms of Resistance
Tuberculosis, Multidrug-Resistant
Isoniazid
Medicine
Humans
2736 Pharmacology (medical)
Pharmacology (medical)
heterocyclic compounds
Amino Acid Sequence
Letter to the Editor
Phylogeny
Pharmacology
biology
business.industry
10179 Institute of Medical Microbiology
Nontuberculous Mycobacteria
Mycobacterium Infections
2725 Infectious Diseases
Mycobacterium tuberculosis
biochemical phenomena, metabolism, and nutrition
biology.organism_classification
bacterial infections and mycoses
Catalase
respiratory tract diseases
Enzyme Activation
Infectious Diseases
3004 Pharmacology
bacteria
570 Life sciences
Nontuberculous mycobacteria
Protein Multimerization
business
Sequence Alignment
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Antimicrob Agents Chemother
- Accession number :
- edsair.doi.dedup.....1102569a72ccde17372caab035c30af6