Emergence of methicillin resistance predates the clinical use of antibiotics

Jesper Larsen; Claire L. Raisen; Xiaoliang Ba; Nicholas J. Sadgrove; Guillermo F. Padilla-González; Monique S.J. Simmonds; Igor Loncaric; Heidrun Kerschner; Petra Apfalter; Rainer Hartl; Ariane Deplano; Stien Vandendriessche; Barbora Černá Bolfíková; Pavel Hulva; Maiken C. Arendrup; Rasmus K. Hare; Céline Barnadas; Marc Stegger; Raphael N. Sieber; Robert L. Skov; Andreas Petersen; Øystein Angen; Sophie L. Rasmussen; Carmen Espinosa-Gongora; Frank M. Aarestrup; Laura J. Lindholm; Suvi M. Nykäsenoja; Frederic Laurent; Karsten Becker; Birgit Walther; Corinna Kehrenberg; Christiane Cuny; Franziska Layer; Guido Werner; Wolfgang Witte; Ivonne Stamm; Paolo Moroni; Hannah J. Jørgensen; Hermínia de Lencastre; Emilia Cercenado; Fernando García-Garrote; Stefan Börjesson; Sara Hæggman; Vincent Perreten; Christopher J. Teale; Andrew S. Waller; Bruno Pichon; Martin D. Curran; Matthew J. Ellington; John J. Welch; Sharon J. Peacock; David J. Seilly; Fiona J.E. Morgan; Julian Parkhill; Nazreen F. Hadjirin; Jodi A. Lindsay; Matthew T.G. Holden; Giles F. Edwards; Geoffrey Foster; Gavin K. Paterson; Xavier Didelot; Mark A. Holmes; Ewan M. Harrison; Anders R. Larsen

doi:10.1038/s41586-021-04265-w

Emergence of methicillin resistance predates the clinical use of antibiotics

Jesper Larsen^*, Claire L. Raisen, Xiaoliang Ba, Nicholas J. Sadgrove, Guillermo F. Padilla-González, Monique S.J. Simmonds, Igor Loncaric, Heidrun Kerschner, Petra Apfalter, Rainer Hartl, Ariane Deplano, Stien Vandendriessche, Barbora Černá Bolfíková, Pavel Hulva, Maiken C. Arendrup, Rasmus K. Hare, Céline Barnadas, Marc Stegger, Raphael N. Sieber, Robert L. SkovAndreas Petersen, Øystein Angen, Sophie L. Rasmussen, Carmen Espinosa-Gongora, Frank M. Aarestrup, Laura J. Lindholm, Suvi M. Nykäsenoja, Frederic Laurent, Karsten Becker, Birgit Walther, Corinna Kehrenberg, Christiane Cuny, Franziska Layer, Guido Werner, Wolfgang Witte, Ivonne Stamm, Paolo Moroni, Hannah J. Jørgensen, Hermínia de Lencastre, Emilia Cercenado, Fernando García-Garrote, Stefan Börjesson, Sara Hæggman, Vincent Perreten, Christopher J. Teale, Andrew S. Waller, Bruno Pichon, Martin D. Curran, Matthew J. Ellington, John J. Welch, Sharon J. Peacock, David J. Seilly, Fiona J.E. Morgan, Julian Parkhill, Nazreen F. Hadjirin, Jodi A. Lindsay, Matthew T.G. Holden, Giles F. Edwards, Geoffrey Foster, Gavin K. Paterson, Xavier Didelot, Mark A. Holmes, Ewan M. Harrison, Anders R. Larsen

^*Corresponding author for this work

UK Health Security Agency

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

149 Citations (Scopus)

Abstract

The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics(1). Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two beta-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

Original language	English
Pages (from-to)	135-141
Number of pages	28
Journal	Nature
Volume	602
Issue number	7895
Early online date	5 Jan 2022
DOIs	https://doi.org/10.1038/s41586-021-04265-w
Publication status	Published - 3 Feb 2022

Bibliographical note

Funding Information:
Acknowledgements We thank M. Ganoti, F. Attila-Zoltán, M. Dugar, Z. Pokorná, D. Madsen, S. M. Gamborg, R. Molina-López, C. Rodrigues, T. Vieira, J. Viricel, A. Fingar, K. South, G. Prince, H. Gasser, S. Sebright, N. Ennew, C. Catchpole, E. Acton, N. Acton, K. Horrey and P. Loague for providing hedgehog samples; A. Medina, L. R. H. Kildevang, P. T. Hansen, and S. M. Johansson for technical assistance during the analysis of hedgehog samples; A. E. Henius for help with Figs. 1, 4 and Extended Data Fig. 8; and V. Bortolaia for reading the manuscript. This work is dedicated to V. R. Simpson, who passed away during the study. B.Č.B. was supported by a grant from the Czech University of Life Sciences Prague (no. IGA 20213106). X.D. was funded by a grant from the National Institute for Health Research (NIHR) Health Protection Research Unit in Genomics and Enabling Data (no. NIHR200892). M.A.H. was supported by grants from the Medical Research Council (nos. G1001787/1, MR/N002660/1 and MR/P007201/1) and the Economic and Social Research Council (no. ES/S000186/1). E.M.H. was supported by a UK Research and Innovation (UKRI) Fellowship (no. MR/S00291X/1). We acknowledge Eurostat for the provision of maps, which are licensed under the Creative Commons Attribution 4.0 International (CC BY 4.0) licence, and administrative boundaries, which are copyright of EuroGeographics.

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© 2022, The Author(s).

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10.1038/s41586-021-04265-w

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Larsen, J., Raisen, C. L., Ba, X., Sadgrove, N. J., Padilla-González, G. F., Simmonds, M. S. J., Loncaric, I., Kerschner, H., Apfalter, P., Hartl, R., Deplano, A., Vandendriessche, S., Černá Bolfíková, B., Hulva, P., Arendrup, M. C., Hare, R. K., Barnadas, C., Stegger, M., Sieber, R. N., ... Larsen, A. R. (2022). Emergence of methicillin resistance predates the clinical use of antibiotics. Nature, 602(7895), 135-141. https://doi.org/10.1038/s41586-021-04265-w

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title = "Emergence of methicillin resistance predates the clinical use of antibiotics",

abstract = "The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics(1). Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two beta-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.",

author = "Jesper Larsen and Raisen, {Claire L.} and Xiaoliang Ba and Sadgrove, {Nicholas J.} and Padilla-Gonz{\'a}lez, {Guillermo F.} and Simmonds, {Monique S.J.} and Igor Loncaric and Heidrun Kerschner and Petra Apfalter and Rainer Hartl and Ariane Deplano and Stien Vandendriessche and {{\v C}ern{\'a} Bolf{\'i}kov{\'a}}, Barbora and Pavel Hulva and Arendrup, {Maiken C.} and Hare, {Rasmus K.} and C{\'e}line Barnadas and Marc Stegger and Sieber, {Raphael N.} and Skov, {Robert L.} and Andreas Petersen and {\O}ystein Angen and Rasmussen, {Sophie L.} and Carmen Espinosa-Gongora and Aarestrup, {Frank M.} and Lindholm, {Laura J.} and Nyk{\"a}senoja, {Suvi M.} and Frederic Laurent and Karsten Becker and Birgit Walther and Corinna Kehrenberg and Christiane Cuny and Franziska Layer and Guido Werner and Wolfgang Witte and Ivonne Stamm and Paolo Moroni and J{\o}rgensen, {Hannah J.} and {de Lencastre}, Herm{\'i}nia and Emilia Cercenado and Fernando Garc{\'i}a-Garrote and Stefan B{\"o}rjesson and Sara H{\ae}ggman and Vincent Perreten and Teale, {Christopher J.} and Waller, {Andrew S.} and Bruno Pichon and Curran, {Martin D.} and Ellington, {Matthew J.} and Welch, {John J.} and Peacock, {Sharon J.} and Seilly, {David J.} and Morgan, {Fiona J.E.} and Julian Parkhill and Hadjirin, {Nazreen F.} and Lindsay, {Jodi A.} and Holden, {Matthew T.G.} and Edwards, {Giles F.} and Geoffrey Foster and Paterson, {Gavin K.} and Xavier Didelot and Holmes, {Mark A.} and Harrison, {Ewan M.} and Larsen, {Anders R.}",

note = "Funding Information: Acknowledgements We thank M. Ganoti, F. Attila-Zolt{\'a}n, M. Dugar, Z. Pokorn{\'a}, D. Madsen, S. M. Gamborg, R. Molina-L{\'o}pez, C. Rodrigues, T. Vieira, J. Viricel, A. Fingar, K. South, G. Prince, H. Gasser, S. Sebright, N. Ennew, C. Catchpole, E. Acton, N. Acton, K. Horrey and P. Loague for providing hedgehog samples; A. Medina, L. R. H. Kildevang, P. T. Hansen, and S. M. Johansson for technical assistance during the analysis of hedgehog samples; A. E. Henius for help with Figs. 1, 4 and Extended Data Fig. 8; and V. Bortolaia for reading the manuscript. This work is dedicated to V. R. Simpson, who passed away during the study. B.{\v C}.B. was supported by a grant from the Czech University of Life Sciences Prague (no. IGA 20213106). X.D. was funded by a grant from the National Institute for Health Research (NIHR) Health Protection Research Unit in Genomics and Enabling Data (no. NIHR200892). M.A.H. was supported by grants from the Medical Research Council (nos. G1001787/1, MR/N002660/1 and MR/P007201/1) and the Economic and Social Research Council (no. ES/S000186/1). E.M.H. was supported by a UK Research and Innovation (UKRI) Fellowship (no. MR/S00291X/1). We acknowledge Eurostat for the provision of maps, which are licensed under the Creative Commons Attribution 4.0 International (CC BY 4.0) licence, and administrative boundaries, which are copyright of EuroGeographics. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41586-021-04265-w",

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Larsen, J, Raisen, CL, Ba, X, Sadgrove, NJ, Padilla-González, GF, Simmonds, MSJ, Loncaric, I, Kerschner, H, Apfalter, P, Hartl, R, Deplano, A, Vandendriessche, S, Černá Bolfíková, B, Hulva, P, Arendrup, MC, Hare, RK, Barnadas, C, Stegger, M, Sieber, RN, Skov, RL, Petersen, A, Angen, Ø, Rasmussen, SL, Espinosa-Gongora, C, Aarestrup, FM, Lindholm, LJ, Nykäsenoja, SM, Laurent, F, Becker, K, Walther, B, Kehrenberg, C, Cuny, C, Layer, F, Werner, G, Witte, W, Stamm, I, Moroni, P, Jørgensen, HJ, de Lencastre, H, Cercenado, E, García-Garrote, F, Börjesson, S, Hæggman, S, Perreten, V, Teale, CJ, Waller, AS, Pichon, B, Curran, MD, Ellington, MJ, Welch, JJ, Peacock, SJ, Seilly, DJ, Morgan, FJE, Parkhill, J, Hadjirin, NF, Lindsay, JA, Holden, MTG, Edwards, GF, Foster, G, Paterson, GK, Didelot, X, Holmes, MA, Harrison, EM & Larsen, AR 2022, 'Emergence of methicillin resistance predates the clinical use of antibiotics', Nature, vol. 602, no. 7895, pp. 135-141. https://doi.org/10.1038/s41586-021-04265-w

TY - JOUR

T1 - Emergence of methicillin resistance predates the clinical use of antibiotics

AU - Larsen, Jesper

AU - Raisen, Claire L.

AU - Ba, Xiaoliang

AU - Sadgrove, Nicholas J.

AU - Padilla-González, Guillermo F.

AU - Simmonds, Monique S.J.

AU - Loncaric, Igor

AU - Kerschner, Heidrun

AU - Apfalter, Petra

AU - Hartl, Rainer

AU - Deplano, Ariane

AU - Vandendriessche, Stien

AU - Černá Bolfíková, Barbora

AU - Hulva, Pavel

AU - Arendrup, Maiken C.

AU - Hare, Rasmus K.

AU - Barnadas, Céline

AU - Stegger, Marc

AU - Sieber, Raphael N.

AU - Skov, Robert L.

AU - Petersen, Andreas

AU - Angen, Øystein

AU - Rasmussen, Sophie L.

AU - Espinosa-Gongora, Carmen

AU - Aarestrup, Frank M.

AU - Lindholm, Laura J.

AU - Nykäsenoja, Suvi M.

AU - Laurent, Frederic

AU - Becker, Karsten

AU - Walther, Birgit

AU - Kehrenberg, Corinna

AU - Cuny, Christiane

AU - Layer, Franziska

AU - Werner, Guido

AU - Witte, Wolfgang

AU - Stamm, Ivonne

AU - Moroni, Paolo

AU - Jørgensen, Hannah J.

AU - de Lencastre, Hermínia

AU - Cercenado, Emilia

AU - García-Garrote, Fernando

AU - Börjesson, Stefan

AU - Hæggman, Sara

AU - Perreten, Vincent

AU - Teale, Christopher J.

AU - Waller, Andrew S.

AU - Pichon, Bruno

AU - Curran, Martin D.

AU - Ellington, Matthew J.

AU - Welch, John J.

AU - Peacock, Sharon J.

AU - Seilly, David J.

AU - Morgan, Fiona J.E.

AU - Parkhill, Julian

AU - Hadjirin, Nazreen F.

AU - Lindsay, Jodi A.

AU - Holden, Matthew T.G.

AU - Edwards, Giles F.

AU - Foster, Geoffrey

AU - Paterson, Gavin K.

AU - Didelot, Xavier

AU - Holmes, Mark A.

AU - Harrison, Ewan M.

AU - Larsen, Anders R.

N1 - Funding Information: Acknowledgements We thank M. Ganoti, F. Attila-Zoltán, M. Dugar, Z. Pokorná, D. Madsen, S. M. Gamborg, R. Molina-López, C. Rodrigues, T. Vieira, J. Viricel, A. Fingar, K. South, G. Prince, H. Gasser, S. Sebright, N. Ennew, C. Catchpole, E. Acton, N. Acton, K. Horrey and P. Loague for providing hedgehog samples; A. Medina, L. R. H. Kildevang, P. T. Hansen, and S. M. Johansson for technical assistance during the analysis of hedgehog samples; A. E. Henius for help with Figs. 1, 4 and Extended Data Fig. 8; and V. Bortolaia for reading the manuscript. This work is dedicated to V. R. Simpson, who passed away during the study. B.Č.B. was supported by a grant from the Czech University of Life Sciences Prague (no. IGA 20213106). X.D. was funded by a grant from the National Institute for Health Research (NIHR) Health Protection Research Unit in Genomics and Enabling Data (no. NIHR200892). M.A.H. was supported by grants from the Medical Research Council (nos. G1001787/1, MR/N002660/1 and MR/P007201/1) and the Economic and Social Research Council (no. ES/S000186/1). E.M.H. was supported by a UK Research and Innovation (UKRI) Fellowship (no. MR/S00291X/1). We acknowledge Eurostat for the provision of maps, which are licensed under the Creative Commons Attribution 4.0 International (CC BY 4.0) licence, and administrative boundaries, which are copyright of EuroGeographics. Publisher Copyright: © 2022, The Author(s).

PY - 2022/2/3

Y1 - 2022/2/3

N2 - The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics(1). Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two beta-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

AB - The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics(1). Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two beta-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.

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U2 - 10.1038/s41586-021-04265-w

DO - 10.1038/s41586-021-04265-w

M3 - Article

AN - SCOPUS:85122332898

SN - 0028-0836

VL - 602

SP - 135

EP - 141

JO - Nature

JF - Nature

IS - 7895

ER -

Emergence of methicillin resistance predates the clinical use of antibiotics

Abstract

Bibliographical note

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