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Decoding a cryptic mechanism of metronidazole resistance among globally disseminated fluoroquinolone-resistant Clostridioides difficile

Author

Listed:
  • Abiola O. Olaitan

    (Texas A&M Health Science Center
    University of Waterloo)

  • Chetna Dureja

    (Texas A&M Health Science Center)

  • Madison A. Youngblom

    (University of Wisconsin-Madison)

  • Madeline A. Topf

    (University of Wisconsin-Madison)

  • Wan-Jou Shen

    (Texas A&M Health Science Center)

  • Anne J. Gonzales-Luna

    (University of Houston College of Pharmacy)

  • Aditi Deshpande

    (Texas A&M Health Science Center)

  • Kirk E. Hevener

    (University of Tennessee Health Science Center)

  • Jane Freeman

    (Leeds Teaching Hospitals Trust
    University of Leeds)

  • Mark H. Wilcox

    (Leeds Teaching Hospitals Trust
    University of Leeds)

  • Kelli L. Palmer

    (University of Texas at Dallas)

  • Kevin W. Garey

    (University of Houston College of Pharmacy)

  • Caitlin S. Pepperell

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Julian G. Hurdle

    (Texas A&M Health Science Center)

Abstract

Severe outbreaks and deaths have been linked to the emergence and global spread of fluoroquinolone-resistant Clostridioides difficile over the past two decades. At the same time, metronidazole, a nitro-containing antibiotic, has shown decreasing clinical efficacy in treating C. difficile infection (CDI). Most metronidazole-resistant C. difficile exhibit an unusual resistance phenotype that can only be detected in susceptibility tests using molecularly intact heme. Here, we describe the mechanism underlying this trait. We find that most metronidazole-resistant C. difficile strains carry a T-to-G mutation (which we term PnimBG) in the promoter of gene nimB, resulting in constitutive transcription. Silencing or deleting nimB eliminates metronidazole resistance. NimB is related to Nim proteins that are known to confer resistance to nitroimidazoles. We show that NimB is a heme-dependent flavin enzyme that degrades nitroimidazoles to amines lacking antimicrobial activity. Furthermore, occurrence of the PnimBG mutation is associated with a Thr82Ile substitution in DNA gyrase that confers fluoroquinolone resistance in epidemic strains. Our findings suggest that the pandemic of fluoroquinolone-resistant C. difficile occurring over the past few decades has also been characterized by widespread resistance to metronidazole.

Suggested Citation

  • Abiola O. Olaitan & Chetna Dureja & Madison A. Youngblom & Madeline A. Topf & Wan-Jou Shen & Anne J. Gonzales-Luna & Aditi Deshpande & Kirk E. Hevener & Jane Freeman & Mark H. Wilcox & Kelli L. Palmer, 2023. "Decoding a cryptic mechanism of metronidazole resistance among globally disseminated fluoroquinolone-resistant Clostridioides difficile," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39429-x
    DOI: 10.1038/s41467-023-39429-x
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    References listed on IDEAS

    as
    1. Ilse M. Boekhoud & Bastian V. H. Hornung & Eloisa Sevilla & Céline Harmanus & Ingrid M. J. G. Bos-Sanders & Elisabeth M. Terveer & Rosa Bolea & Jeroen Corver & Ed J. Kuijper & Wiep Klaas Smits, 2020. "Plasmid-mediated metronidazole resistance in Clostridioides difficile," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
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