Journal article
Loss of methyltransferase function and increased efflux activity leads to doxycycline resistance in Burkholderia pseudomallei
Antimicrobial Agents and Chemotherapy, Vol.61(6), e0026817
2017
Abstract
The soil-dwelling bacterium Burkholderia pseudomallei is the causative agent of the potentially fatal disease melioidosis. The lack of a vaccine towards B. pseudomallei means that melioidosis treatment relies on prolonged antibiotic therapy, which can last up to six months in duration or longer. Due to intrinsic resistance, few antibiotics are effective against B. pseudomallei. The lengthy treatment regimen required increases the likelihood of resistance development, with subsequent potentially fatal relapse. Doxycycline (DOX) has historically played an important role in the eradication phase of melioidosis treatment. Both primary and acquired DOX resistance have been documented in B. pseudomallei; however, the molecular mechanisms underpinning DOX resistance have remained elusive. Here we identify and functionally characterize the molecular mechanisms conferring acquired DOX resistance in an isogenic B. pseudomallei pair. Two synergistic mechanisms were identified. The first mutation occurred in a putative S-adenosyl-L-methionine-dependent methyltransferase (encoded by BPSL3085), which we propose leads to altered ribosomal methylation, thereby decreasing DOX-binding efficiency. The second mutation altered the function of the efflux pump repressor gene amrR, resulting in increased expression of the resistance-nodulation-division efflux pump, AmrAB-OprA. Our findings highlight the diverse mechanisms by which B. pseudomallei can become resistant to antibiotics used in melioidosis therapy and the need for resistance monitoring during treatment regimens, especially in patients with prolonged or recrudesced positive cultures for B. pseudomallei.
Details
- Title
- Loss of methyltransferase function and increased efflux activity leads to doxycycline resistance in Burkholderia pseudomallei
- Authors
- Jessica R Webb (Author) - Menzies School of Health ResearchErin P Price (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and EngineeringBart J Currie (Author) - Menzies School of Health ResearchDerek S Sarovich (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and Engineering
- Publication details
- Antimicrobial Agents and Chemotherapy, Vol.61(6), e0026817; 11
- Publisher
- American Society for Microbiology
- Date published
- 2017
- DOI
- 10.1128/AAC.00268-17
- ISSN
- 0066-4804
- Copyright note
- Copyright © 2017 American Society for Microbiology. The author's accepted version is reproduced here in accordance with the publisher's copyright policy. The definitive version is available at http://aem.asm.org/
- Organisation Unit
- University of the Sunshine Coast, Queensland; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99451067702621
- Output Type
- Journal article
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- Microbiology
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