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

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, Kevin W. Garey, Caitlin S. Pepperell () and Julian G. Hurdle ()
Additional contact information
Abiola O. Olaitan: Texas A&M Health Science Center
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
Mark H. Wilcox: Leeds Teaching Hospitals Trust
Kelli L. Palmer: University of Texas at Dallas
Kevin W. Garey: University of Houston College of Pharmacy
Caitlin S. Pepperell: University of Wisconsin-Madison
Julian G. Hurdle: Texas A&M Health Science Center

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39429-x

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