Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Punyawee Dulyayangkul; Thomas Beavis; Winnie W Y Lee; Robbie Ardagh; Frances Edwards; Fergus Hamilton; Ian Head; Kate J Heesom; Oliver Mounsey; Marek Murarik; Peechanika Pinweha; Carlos Reding; Naphat Satapoomin; John M Shaw; Yuiko Takebayashi; Catherine L Tooke; James Spencer; Philip B Williams; Matthew B Avison

doi:10.1371/journal.ppat.1012235

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Punyawee Dulyayangkul, Thomas Beavis, Winnie W Y Lee, Robbie Ardagh, Frances Edwards, Fergus Hamilton, Ian Head, Kate J Heesom, Oliver Mounsey, Marek Murarik, Peechanika Pinweha, Carlos Reding, Naphat Satapoomin, John M Shaw, Yuiko Takebayashi, Catherine L Tooke, James Spencer, Philip B Williams, Matthew B Avison

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (SciVal)

Abstract

Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been "harvested" by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6')-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.

Original language	English
Article number	e1012235
Journal	PLoS Pathogens
Volume	20
Issue number	6
DOIs	https://doi.org/10.1371/journal.ppat.1012235
Publication status	Published - 6 Jun 2024

Data Availability Statement

All genome sequence data have been deposited onto the European Nucleotide Sequence Archive (ENA) under accession number PRJEB73531.

Funding

This work was funded by Medical Research Council grants MR/T005408/1 (to P.B.W. and M.B.A), MR/N013646/1 (to M.B.A. and K.J.H.) and MR/S004769/1 (to M.B.A) and by Natural Environment Research Council grant NE/N01961X/ 1 (to M.B.A.), by grant 82459 (to M.B.A.) from the Welsh Government Rural Communities - Rural Development Programme 2014-2020 supported by the European Union and the Welsh Government (Llywodraeth Cymru). W.W.Y.L. received a scholarship from the Medical Research Foundation National PhD Training Program in Antimicrobial Resistance Research (MRF-145-0004-TPGAVISO). Clinical training fellowships were funded by the Wellcome Trust (to F.E. and F.H) and National Institute for Health Research (to I.H.). P.P. was supported by a Royal Thai Government scholarship. N.S. was supported by a postgraduate scholarship from the University of Bristol. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No author received a salary directly from any funder. We are grateful to laboratory staff at Severn Pathology, North Bristol NHS Trust, for collecting the bloodstream isolates, and to Dr Jacqueline Findlay, formerly of the School of Cellular & Molecular Medicine, University of Bristol, for preparing the 2018 isolates for sequencing. WGS was performed by MicrobesNG, Birmingham, UK. We are indebted to Dr Tara deBoer and particularly to Dr Nicole Jackson, BioAmp Diagnostics for provision of isolate-specific susceptibility testing data essential for our secondary analysis of their publicly available genome sequence data.

Funders	Funder number
National Institute for Health and Care Research
European Commission
The Wellcome Trust
School of Cellular & Molecular Medicine, University of Bristol
North Bristol NHS Trust
Royal Thai Government
University of Bristol
Welsh Government Rural Communities
Medical Research Council	MR/T005408/1, MR/S004769/1, MR/N013646/1
Natural Environment Research Council	82459, NE/N01961X/ 1
Llywodraeth Cymru	MRF-145-0004-TPGAVISO

Keywords

Humans
Anti-Bacterial Agents/pharmacology
DNA Transposable Elements/genetics
Drug Resistance, Multiple, Bacterial/genetics
Piperacillin/pharmacology
Amikacin/pharmacology
Microbial Sensitivity Tests
Enterobacteriaceae Infections/microbiology
Enterobacteriaceae/genetics
Integrons/genetics
Bacteremia/microbiology

ASJC Scopus subject areas

Parasitology
Microbiology
Immunology
Molecular Biology
Genetics
Virology

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Cite this

Dulyayangkul, P., Beavis, T., Lee, W. W. Y., Ardagh, R., Edwards, F., Hamilton, F., Head, I., Heesom, K. J., Mounsey, O., Murarik, M., Pinweha, P., Reding, C., Satapoomin, N., Shaw, J. M., Takebayashi, Y., Tooke, C. L., Spencer, J., Williams, P. B., & Avison, M. B. (2024). Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics. PLoS Pathogens, 20(6 ), Article e1012235. https://doi.org/10.1371/journal.ppat.1012235

Dulyayangkul, P, Beavis, T, Lee, WWY, Ardagh, R, Edwards, F, Hamilton, F, Head, I, Heesom, KJ, Mounsey, O, Murarik, M, Pinweha, P, Reding, C, Satapoomin, N, Shaw, JM, Takebayashi, Y, Tooke, CL, Spencer, J, Williams, PB & Avison, MB 2024, 'Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics', PLoS Pathogens, vol. 20, no. 6 , e1012235. https://doi.org/10.1371/journal.ppat.1012235

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abstract = "Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been {"}harvested{"} by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6')-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.",

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AU - Edwards, Frances

AU - Hamilton, Fergus

AU - Head, Ian

AU - Heesom, Kate J

AU - Mounsey, Oliver

AU - Murarik, Marek

AU - Pinweha, Peechanika

AU - Reding, Carlos

AU - Satapoomin, Naphat

AU - Shaw, John M

AU - Takebayashi, Yuiko

AU - Tooke, Catherine L

AU - Spencer, James

AU - Williams, Philip B

AU - Avison, Matthew B

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AB - Amikacin and piperacillin/tazobactam are frequent antibiotic choices to treat bloodstream infection, which is commonly fatal and most often caused by bacteria from the family Enterobacterales. Here we show that two gene cassettes located side-by-side in and ancestral integron similar to In37 have been "harvested" by insertion sequence IS26 as a transposon that is widely disseminated among the Enterobacterales. This transposon encodes the enzymes AAC(6')-Ib-cr and OXA-1, reported, respectively, as amikacin and piperacillin/tazobactam resistance mechanisms. However, by studying bloodstream infection isolates from 769 patients from three hospitals serving a population of 1.2 million people in South West England, we show that increased enzyme production due to mutation in an IS26/In37-derived hybrid promoter or, more commonly, increased transposon copy number is required to simultaneously remove these two key therapeutic options; in many cases leaving only the last-resort antibiotic, meropenem. These findings may help improve the accuracy of predicting piperacillin/tazobactam treatment failure, allowing stratification of patients to receive meropenem or piperacillin/tazobactam, which may improve outcome and slow the emergence of meropenem resistance.

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KW - Anti-Bacterial Agents/pharmacology

KW - DNA Transposable Elements/genetics

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JO - PLoS Pathogens

JF - PLoS Pathogens

IS - 6

M1 - e1012235

ER -

Harvesting and amplifying gene cassettes confers cross-resistance to critically important antibiotics

Abstract

Data Availability Statement

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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