Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 63, Issue 8, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00292-19
Keywords
Mycobacterium tuberculosis; atpE; bedaquiline; in vitro model; rv0678; stepwise acquisition
Categories
Funding
- National Research Fund [SFH150723130071]
- University of Pretoria
- Centre for Tuberculosis (WHO TB Supranational Reference Laboratory) at the National Institute for Communicable Diseases (NHLS) [GRANT004_ 94640]
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Bedaquiline resistance within Mycobacterium tuberculosis may arise through efflux-based (rv0678) or target-based (atpE) pathway mutations. M. tuberculosis mutant populations from each of five sequential steps in a passaging approach, using a pyrazinamide-resistant ATCC strain, were subjected to MIC determinations and whole-genome sequencing. Exposure to increasing bedaquiline concentrations resulted in increasing phenotypic resistance (up to >2 mu g/ml) through MIC determination on solid medium (Middlebrook 7H10). rv0678 mutations were dynamic, while atpE mutations were fixed, once occurring. We present the following hypothesis for in vitro emergence of bedaquiline resistance: rv0678 mutations may be the first transient step in low-level resistance acquisition, followed by high-level resistance due to fixed otpE mutations.
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