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Heme is crucial for medium-dependent metronidazole resistance in clinical isolates of C. difficile

View ORCID ProfileIlse M. Boekhoud, View ORCID ProfileIgor Sidorov, View ORCID ProfileSam Nooij, View ORCID ProfileCéline Harmanus, Ingrid M.J.G. Bos-Sanders, Virginie Viprey, Bill Spittal, Emma Clark, View ORCID ProfileKerrie Davies, View ORCID ProfileJane Freeman, View ORCID ProfileEd J. Kuijper, View ORCID ProfileWiep Klaas Smits
doi: https://doi.org/10.1101/2020.11.18.388959
Ilse M. Boekhoud
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
2Netherlands Centre for One Health, The Netherlands
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Igor Sidorov
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Sam Nooij
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
3Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
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Céline Harmanus
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Ingrid M.J.G. Bos-Sanders
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Virginie Viprey
4Healthcare Associated Infections Research Group, School of Medicine, University of Leeds, Leeds, United Kingdom
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Bill Spittal
4Healthcare Associated Infections Research Group, School of Medicine, University of Leeds, Leeds, United Kingdom
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Emma Clark
4Healthcare Associated Infections Research Group, School of Medicine, University of Leeds, Leeds, United Kingdom
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Kerrie Davies
4Healthcare Associated Infections Research Group, School of Medicine, University of Leeds, Leeds, United Kingdom
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  • ORCID record for Kerrie Davies
Jane Freeman
4Healthcare Associated Infections Research Group, School of Medicine, University of Leeds, Leeds, United Kingdom
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Ed J. Kuijper
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
5National Institute for Public Health and the Environment, Bilthoven, The Netherlands
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Wiep Klaas Smits
1Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
2Netherlands Centre for One Health, The Netherlands
3Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands
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  • For correspondence: w.k.smits@lumc.nl
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Abstract

Until recently, metronidazole was the first-line treatment for Clostridioides difficile infection and it is still commonly used. Though resistance has been reported due to the plasmid pCD-METRO, this does not explain all cases. Here, we investigate resistance to metronidazole in a collection of clinical isolates of C. difficile. We find that nearly all isolates demonstrate a heme-dependent increase in the minimal inhibitory concentration for metronidazole, which in some cases leads to isolates being qualified as resistant (MIC > 2 mg/L). Moreover, whole genome sequence analysis reveals a single nucleotide polymorphism in the heme responsive gene hsmA, which defines a metronidazole resistant lineage of PCR ribotype 010 / multilocus sequence type 15 isolates that also includes pCD-METRO containing strains. Together our data demonstrate that heme is crucial for medium-dependent metronidazole resistance in C. difficile.

Competing Interest Statement

The COMBACTE-CDI consortium includes partners GSK, Pfizer, DaVolterra, AstraZeneca, Sanofi Pasteur and bioMerieux. The companies did not have a role in the design and execution of the experiments for this study but provided the WGS of the isolates (GSK) and allowed examination of the FASTQ files (bioMerieux).

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 18, 2020.
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Heme is crucial for medium-dependent metronidazole resistance in clinical isolates of C. difficile
Ilse M. Boekhoud, Igor Sidorov, Sam Nooij, Céline Harmanus, Ingrid M.J.G. Bos-Sanders, Virginie Viprey, Bill Spittal, Emma Clark, Kerrie Davies, Jane Freeman, Ed J. Kuijper, Wiep Klaas Smits
bioRxiv 2020.11.18.388959; doi: https://doi.org/10.1101/2020.11.18.388959
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Heme is crucial for medium-dependent metronidazole resistance in clinical isolates of C. difficile
Ilse M. Boekhoud, Igor Sidorov, Sam Nooij, Céline Harmanus, Ingrid M.J.G. Bos-Sanders, Virginie Viprey, Bill Spittal, Emma Clark, Kerrie Davies, Jane Freeman, Ed J. Kuijper, Wiep Klaas Smits
bioRxiv 2020.11.18.388959; doi: https://doi.org/10.1101/2020.11.18.388959

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