Plasmid-mediated metronidazole resistance in Clostridioides difficile

• Published in: Nature communications Vol. 11; no. 1; pp. 598 - 12
• Main Authors: Boekhoud, Ilse M., Hornung, Bastian V. H., Sevilla, Eloisa, Harmanus, Céline, Bos-Sanders, Ingrid M. J. G., Terveer, Elisabeth M., Bolea, Rosa, Corver, Jeroen, Kuijper, Ed J., Smits, Wiep Klaas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/22; 42; 42/44; 45/23; 45/77; 631/326/22/1434; 631/326/2521; 631/326/325/2482; 692/4020/1503/1581/1422; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial resistance; Clostridioides difficile - drug effects; Clostridioides difficile - genetics; Clostridioides difficile - growth & development; Clostridioides difficile - physiology; Clostridium Infections - drug therapy; Clostridium Infections - microbiology; DNA, Bacterial - genetics; Drug Resistance, Bacterial - drug effects; Drug Resistance, Bacterial - genetics; Feces - microbiology; Gene Dosage; Gene sequencing; Gene Transfer, Horizontal - genetics; Genomes; Humanities and Social Sciences; Humans; Impact resistance; Metronidazole; Metronidazole - pharmacology; Metronidazole - therapeutic use; Minimum inhibitory concentration; multidisciplinary; Plasmids; Plasmids - genetics; Polymorphism, Single Nucleotide - genetics; Recurrent infection; Replicon - genetics; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14382-1

Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection. Although cases of metronidazole resistance have been documented, no clear mechanism for metronidazole resistance or a role for plasmids in antimicrobial resistance has been described for CD. Here, we report genome sequences of seven susceptible and sixteen resistant CD isolates from human and animal sources, including isolates from a patient with recurrent CD infection by a PCR ribotype (RT) 020 strain, which developed resistance to metronidazole over the course of treatment (minimal inhibitory concentration [MIC] = 8 mg L −1 ). Metronidazole resistance correlates with the presence of a 7-kb plasmid, pCD-METRO. pCD-METRO is present in toxigenic and non-toxigenic resistant ( n  = 23), but not susceptible ( n  = 563), isolates from multiple countries. Introduction of a pCD-METRO-derived vector into a susceptible strain increases the MIC 25-fold. Our finding of plasmid-mediated resistance can impact diagnostics and treatment of CD infections. Cases of C. difficile (CD) resistant to metronidazole have been reported but the mechanism remains enigmatic. Here the authors identify a plasmid, which correlates with metronidazole resistance status in a large international collection of CD isolates, and demonstrate that the plasmid can confer metronidazole resistance.