| Autor: |
Alexander, David C., Vasireddy, Ravikiran, Vasireddy, Sruthi, Philley, Julie V., Brown-Elliott, Barbara A., Perry, Benjamin J., Griffith, David E., Benwill, Jeana L., Cameron, Andrew D. S., Wallace, Richard J. |
| Zdroj: |
Journal of Clinical Microbiology; December 2016, Vol. 55 Issue: 2 p574-584, 11p |
| Abstrakt: |
ABSTRACTBedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosisinfections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellularelung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulareuncovered mutations in a previously uncharacterized locus, mmpT5. Preliminary analysis suggested similarities between mmpT5and the mmpR5locus, which is associated with low-level BDQ resistance in M. tuberculosis. Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5mutations are associated with modest 2- to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpEmutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellularelung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5variants and microbiological relapse. |
| Databáze: |
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