Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei: Deviation from the norm

Nicole L. Podnecky , Katherine A. Rhodes, Takehiko Mima, Heather R. Drew, Sunisa Chirakul , Vanaporn Wuthiekanun, James Schupp, Derek Sarovich, Bart Currie, Paul Keim, Herbert P. Schweitzer

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    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 cotrimoxazole 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 cotrimoxazole 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. Cotrimoxazole resistance in B. pseudomallei is a complex phenomenon, which may explain why resistance to this drug is rare in this bacterium.
    Original languageEnglish
    Article numbere01357-17
    Pages (from-to)1-18
    Number of pages18
    JournalmBio
    Volume8
    Issue number5
    DOIs
    Publication statusPublished - 5 Sep 2017

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    Podnecky , N. L., Rhodes, K. A., Mima, T., Drew, H. R., Chirakul , S., Wuthiekanun, V., Schupp, J., Sarovich, D., Currie, B., Keim, P., & Schweitzer, H. P. (2017). Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei: Deviation from the norm. mBio, 8(5), 1-18. [e01357-17]. https://doi.org/10.1128/mBio.01357-17