Journal article
Mechanisms of Resistance to Folate Pathway Inhibitors in Burkholderia pseudomallei: Deviation from the Norm
mBio, Vol.8(5), e01357-17
2017
Abstract
The trimethoprim and sulfamethoxazole combination, co-trimoxazole, plays a vital role in the treatment of Burkholderia pseudomallei infections. Previous studies demonstrated that the B. pseudomallei BpeEF-OprC efflux pump confers widespread trimethoprim resistance in clinical and environmental isolates, but this is not accompanied by significant resistance to co-trimoxazole. Using the excluded select-agent strain B. pseudomallei Bp82, we now show that in vitro acquired trimethoprim versus co-trimoxazole resistance is mainly mediated by constitutive BpeEF-OprC expression due to bpeT mutations or by BpeEF-OprC overexpression due to bpeS mutations. Mutations in bpeT affect the carboxy-terminal effector-binding domain of the BpeT LysR-type activator protein. Trimethoprim resistance can also be mediated by dihydrofolate reductase (FolA) target mutations, but this occurs rarely unless BpeEF-OprC is absent. BpeS is a transcriptional regulator that is 62% identical to BpeT. Mutations affecting the BpeS DNA-binding or carboxy-terminal effector-binding domains result in constitutive BpeEF-OprC overexpression, leading to trimethoprim and sulfamethoxazole efflux and thus to co-trimoxazole resistance. The majority of laboratory-selected co-trimoxazole-resistant mutants often also contain mutations in folM, encoding a pterin reductase. Genetic analyses of these mutants established that both bpeS mutations and folM mutations contribute to co-trimoxazole resistance, although the exact role of folM remains to be determined. Mutations affecting bpeT, bpeS, and folM are common in co-trimoxazole-resistant clinical isolates, indicating that mutations affecting these genes are clinically significant. Co-trimoxazole resistance in B. pseudomallei is a complex phenomenon, which may explain why resistance to this drug is rare in this bacterium.
Details
- Title
- Mechanisms of Resistance to Folate Pathway Inhibitors in Burkholderia pseudomallei: Deviation from the Norm
- Authors
- Nicole L Podnecky (Author) - Colorado State University, United StatesKatherine A Rhodes (Author) - Colorado State University, United StatesTakehiko Mima (Author) - Colorado State University, United StatesHeather R Drew (Author) - University of Florida, United StatesSunisa Chirakul (Author) - University of Florida, United StatesVanaporn Wuthiekanun (Author) - Mahidol University, ThailandJames M Schupp (Author) - Translational Genomics Research Institute, United StatesDerek S Sarovich (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and EngineeringBart J Currie (Author) - Menzies School of Health ResearchPaul Kaim (Author) - Northern Arizona University, United StatesHerbert P Schweiser (Corresponding Author) - Colorado State University, United States
- Publication details
- mBio, Vol.8(5), e01357-17; 18
- Publisher
- American Society for Microbiology
- Date published
- 2017
- DOI
- 10.1128/mBio.01357-17
- ISSN
- 2161-2129; 2150-7511
- Copyright note
- Copyright © 2017 Podnecky et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license
- Organisation Unit
- University of the Sunshine Coast, Queensland; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99450911202621
- Output Type
- Journal article
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