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Demonstrating a Multi-drug Resistant Mycobacterium tuberculosis Amplification Microarray
Published on: April 25, 2014
embCAB sequence variation among ethambutol-resistant Mycobacterium tuberculosis isolates without embB306 mutation
Claudia Plinke1, Helen S Cox, Nana Zarkua
1Molecular Mycobacteriology, Research Center Borstel, Borstel, Germany.
The Journal of Antimicrobial Chemotherapy
|April 30, 2010
Summary
New research reveals that mutations beyond codon 306 in the embB gene are key to ethambutol resistance in Mycobacterium tuberculosis. Identifying these mutations aids in developing rapid diagnostic tests for drug-resistant tuberculosis.
Area of Science:
- Microbiology
- Genetics
- Molecular Biology
Background:
- Mechanisms of ethambutol resistance in Mycobacterium tuberculosis (M. tuberculosis) are not fully understood.
- While mutations in embB codon 306 are implicated, many resistant strains lack this mutation, suggesting other genetic factors are involved.
- The embCAB operon is a potential source of alternative resistance mechanisms.
Purpose of the Study:
- To investigate mutations within the entire embCAB operon in ethambutol-resistant M. tuberculosis strains lacking embB306 mutations.
- To identify novel genetic determinants of ethambutol resistance in M. tuberculosis.
- To assess the potential of specific embB regions as targets for rapid molecular diagnostics.
Main Methods:
- Whole-operon sequencing of the embCAB operon (approximately 10 kb) was performed on 34 ethambutol-resistant M. tuberculosis strains lacking embB306 mutations and 12 ethambutol-susceptible strains.
- An additional 106 control strains were analyzed for specific identified mutations.
- Comparative analysis was conducted to identify mutations present in resistant strains but absent in susceptible strains.
Main Results:
- Eighteen non-synonymous mutations in 15 distinct codons of the embCAB operon were identified exclusively in ethambutol-resistant strains.
- The majority of these mutations were located in the embB gene, particularly within a 570 bp region encompassing embB306.
- Mutations in embC and embA were infrequent and often co-occurred with embB polymorphisms. Specific mutations were linked to M. tuberculosis genotypes (Beijing, Haarlem, Delhi/CAS).
Conclusions:
- Mutations in embB codons 406 and 497 are significant 'hot spots' for genomic variation associated with ethambutol resistance in clinical M. tuberculosis isolates.
- A substantial proportion (70.6%) of ethambutol-resistant strains harbor mutations within a defined, short region of the embB gene.
- This specific embB region represents a promising target for developing rapid molecular assays for ethambutol resistance detection.
