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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    Burkholderia pseudomallei
    Sulfamethoxazole Drug Combination Trimethoprim
    Folic Acid
    Mutation
    Trimethoprim Resistance
    Burkholderia Infections
    Pterins
    Tetrahydrofolate Dehydrogenase
    Trimethoprim
    Drug Resistance
    Oxidoreductases

    Cite this

    Podnecky , N. L., Rhodes, K. A., Mima, T., Drew, H. R., Chirakul , S., Wuthiekanun, V., ... 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
    Podnecky , Nicole L. ; Rhodes, Katherine A. ; Mima, Takehiko ; Drew, Heather R. ; Chirakul , Sunisa ; Wuthiekanun, Vanaporn ; Schupp, James ; Sarovich, Derek ; Currie, Bart ; Keim, Paul ; Schweitzer, Herbert P. / Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei : Deviation from the norm. In: mBio. 2017 ; Vol. 8, No. 5. pp. 1-18.
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    title = "Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei: Deviation from the norm",
    abstract = "The trimethoprim and sulfamethoxazole combination, co-trimoxazole, playsa 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 contributeto 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.",
    author = "Podnecky, {Nicole L.} and Rhodes, {Katherine A.} and Takehiko Mima and Drew, {Heather R.} and Sunisa Chirakul and Vanaporn Wuthiekanun and James Schupp and Derek Sarovich and Bart Currie and Paul Keim and Schweitzer, {Herbert P.}",
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    Podnecky , NL, Rhodes, KA, Mima, T, Drew, HR, Chirakul , S, Wuthiekanun, V, Schupp, J, Sarovich, D, Currie, B, Keim, P & Schweitzer, HP 2017, 'Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei: Deviation from the norm', mBio, vol. 8, no. 5, e01357-17, pp. 1-18. https://doi.org/10.1128/mBio.01357-17

    Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei : Deviation from the norm. / Podnecky , Nicole L.; Rhodes, Katherine A.; Mima, Takehiko; Drew, Heather R.; Chirakul , Sunisa; Wuthiekanun, Vanaporn; Schupp, James; Sarovich, Derek; Currie, Bart; Keim, Paul; Schweitzer, Herbert P.

    In: mBio, Vol. 8, No. 5, e01357-17, 05.09.2017, p. 1-18.

    Research output: Contribution to journalArticleResearchpeer-review

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    AU - Podnecky , Nicole L.

    AU - Rhodes, Katherine A.

    AU - Mima, Takehiko

    AU - Drew, Heather R.

    AU - Chirakul , Sunisa

    AU - Wuthiekanun, Vanaporn

    AU - Schupp, James

    AU - Sarovich, Derek

    AU - Currie, Bart

    AU - Keim, Paul

    AU - Schweitzer, Herbert P.

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    Podnecky NL, Rhodes KA, Mima T, Drew HR, Chirakul S, Wuthiekanun V et al. Mechanisms of resistance to folate pathway inhibitors in Burkholderia pseudomallei: Deviation from the norm. mBio. 2017 Sep 5;8(5):1-18. e01357-17. https://doi.org/10.1128/mBio.01357-17