Imperial College London
Alternate

DrXavierDidelot

Faculty of Medicine, School of Public Health

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3622x.didelot

 
 
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Location

 

G30Medical SchoolSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Dingle:2022:10.1101/2022.05.23.493179,
author = {Dingle, KE and Freeman, J and Didelot, X and Eyre, DW and Swan, J and Spittal, WD and Clark, EV and Jolley, KA and Sarah, Walker A and Wilcox, MH and Crook, DW},
doi = {10.1101/2022.05.23.493179},
title = {Penicillin Binding Protein Substitutions Co-occur with Fluoroquinolone Resistance in ‘Epidemic’ Lineages of Multi Drug-Resistant <i>Clostridioides difficile</i>},
url = {http://dx.doi.org/10.1101/2022.05.23.493179},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - <jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Clostridioides difficile</jats:italic> remains a key cause of healthcare-associated infection, with multi-drug-resistant (MDR) lineages causing high mortality (≥20%) outbreaks. Cephalosporin treatment is a long-established risk factor, and antimicrobial stewardship a key control. A mechanism underlying raised cephalosporin MICs has not been identified in <jats:italic>C. difficile</jats:italic>, but among other species resistance is often acquired <jats:italic>via</jats:italic> amino acid substitutions in cell wall transpeptidases (penicillin binding proteins, PBPs). Here, we investigated five <jats:italic>C. difficile</jats:italic> transpeptidases (PBP1-5) for recent substitutions. Previously published genome assemblies (n=7096) were obtained, representing sixteen geographically widespread lineages, including healthcare-associated MDR ST1(027), ST3(001) and ST17(018). Recent amino acid substitutions were found within PBP1 (n=50) and PBP3 (n=48), ranging from 1-10 substitutions per genome. β-lactam MICs were measured for closely related pairs of wild-type and PBP substituted isolates separated by 20-273 SNPs. Recombination-corrected, dated phylogenies were constructed to date substitution acquisition. Key substitutions such as PBP3 V497L and PBP1 T674I/N/V emerged independently across multiple lineages. They were associated with extremely high cephalosporin MICs; 1-4 doubling dilutions >wild-type up to ≤1506μg/ml. Substitution patterns varied by lineage and clade, showed geographic structure, and notably occurred post-1990, coincident with the acquisition of <jats:italic>gyrA</jats:italic>/<jats:italic>B</jats:italic> substitutions conferring fluoroquinolone resistance. In conclusion, recent PBP1 and PBP3 substitutions are associated with raised cephalosporin MICs in <jats:italic>C. difficile</ja
AU  - Dingle,KE
AU  - Freeman,J
AU  - Didelot,X
AU  - Eyre,DW
AU  - Swan,J
AU  - Spittal,WD
AU  - Clark,EV
AU  - Jolley,KA
AU  - Sarah,Walker A
AU  - Wilcox,MH
AU  - Crook,DW
DO  - 10.1101/2022.05.23.493179
PY  - 2022///
TI  - Penicillin Binding Protein Substitutions Co-occur with Fluoroquinolone Resistance in ‘Epidemic’ Lineages of Multi Drug-Resistant <i>Clostridioides difficile</i>
UR  - http://dx.doi.org/10.1101/2022.05.23.493179
ER  -
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