Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus

Abstract

Antibiotic resistance in bacterial pathogens threatens the future of modern medicine. One such resistant pathogen is methicillin-resistant Staphylococcus aureus (MRSA), which is resistant to nearly all β-lactam antibiotics, limiting treatment options. Here, we show that a significant proportion of MRSA isolates from different lineages, including the epidemic USA300 lineage, are susceptible to penicillins when used in combination with β-lactamase inhibitors such as clavulanic acid. Susceptibility is mediated by a combination of two different mutations in the mecA promoter region that lowers mecA-encoded penicillin-binding protein 2a (PBP2a) expression, and in the majority of isolates by either one of two substitutions in PBP2a (E246G or M122I) that increase the affinity of PBP2a for penicillin in the presence of clavulanic acid. Treatment of S. aureus infections in wax moth and mouse models shows that penicillin/β-lactamase inhibitor susceptibility can be exploited as an effective therapeutic choice for ‘susceptible’ MRSA infection. Finally, we show that isolates with the PBP2a E246G substitution have a growth advantage in the presence of penicillin but the absence of clavulanic acid, which suggests that penicillin/β-lactamase susceptibility is an example of collateral sensitivity (resistance to one antibiotic increases sensitivity to another). Our findings suggest that widely available and currently disregarded antibiotics could be effective in a significant proportion of MRSA infections.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Penicillin susceptibility in the presence of clavulanic acid.
Fig. 2: PBP2a substitutions mediating penicillin susceptibility.
Fig. 3: Genetic basis of MRSA penicillin/clavulanic acid susceptibility.
Fig. 4: Prevalence and population genomics of penicillin–clavulanic acid.
Fig. 5: Penicillins and clavulanic acid are efficacious for the treatment of susceptible MRSA.
Fig. 6: PBP2a246G substitution provides an increased growth rate in the presence of penicillin.

Data availability

All data generated or analysed during this study are included in the published article and its Supplementary Information files.

References

  1. 1.

    Worthington, R. J. & Melander, C. Overcoming resistance to β-lactam antibiotics. J. Org. Chem. 78, 4207–4213 (2013).

    CAS  Article  Google Scholar 

  2. 2.

    Hartman, B. J. & Tomasz, A. Low-affinity penicillin-binding protein associated with β-lactam resistance in Staphylococcus aureus. J. Bacteriol. 158, 513–516 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Katayama, Y., Ito, T. & Hiramatsu, K. A new class of genetic element, Staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 44, 1549–1555 (2000).

    CAS  Article  Google Scholar 

  4. 4.

    Garcia-Alvarez, L. et al. Meticillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: a descriptive study. Lancet Infect. Dis. 11, 595–603 (2011).

    CAS  Article  Google Scholar 

  5. 5.

    Aedo, S. & Tomasz, A. Role of the stringent stress response in the antibiotic resistance phenotype of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 60, 2311–2317 (2016).

    CAS  Article  Google Scholar 

  6. 6.

    Rolinson, G. N., Stevens, S., Batchelor, F. R., Wood, J. C. & Chain, E. B. Bacteriological studies on a new penicillin—BRL.1241. Lancet 2, 564–567 (1960).

    CAS  Article  Google Scholar 

  7. 7.

    Reading, C. & Cole, M. Clavulanic acid: a β-lactamase-inhibiting β-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 11, 852–857 (1977).

    CAS  Article  Google Scholar 

  8. 8.

    Chambers, H. F., Kartalija, M. & Sande, M. Ampicillin, sulbactam, and rifampin combination treatment of experimental methicillin-resistant Staphylococcus aureus endocarditis in rabbits. J. Infect. Dis. 171, 897–902 (1995).

    CAS  Article  Google Scholar 

  9. 9.

    Chambers, H. F., Sachdeva, M. & Kennedy, S. Binding affinity for penicillin-binding protein 2a correlates with in vivo activity of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 162, 705–710 (1990).

    CAS  Article  Google Scholar 

  10. 10.

    Washburn, R. G. & Durack, D. T. Efficacy of ampicillin plus a β-lactamase inhibitor (CP-45,899) in experimental endocarditis due to Staphylococcus aureus. J. Infect. Dis. 144, 237–243 (1981).

    CAS  Article  Google Scholar 

  11. 11.

    Cantoni, L., Wenger, A., Glauser, M. P. & Bille, J. Comparative efficacy of amoxicillin-clavulanate, cloxacillin, and vancomycin against methicillin-sensitive and methicillin-resistant Staphylococcus aureus endocarditis in rats. J. Infect. Dis. 159, 989–993 (1989).

    CAS  Article  Google Scholar 

  12. 12.

    Guignard, B., Entenza, J. M. & Moreillon, P. β-lactams against methicillin-resistant Staphylococcus aureus. Curr. Opin. Pharmacol. 5, 479–489 (2005).

    CAS  Article  Google Scholar 

  13. 13.

    Tan, C. M. et al. Restoring methicillin-resistant Staphylococcus aureus susceptibility to β-lactam antibiotics. Sci. Transl. Med. 4, 126ra135 (2012).

    Google Scholar 

  14. 14.

    Lee, S. H. et al. TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci. Sci. Transl. Med. 8, 329ra332 (2016).

    Article  Google Scholar 

  15. 15.

    Klitgaard, J. K., Skov, M. N., Kallipolitis, B. H. & Kolmos, H. J. Reversal of methicillin resistance in Staphylococcus aureus by thioridazine. J. Antimicrob. Chemother. 62, 1215–1221 (2008).

    CAS  Article  Google Scholar 

  16. 16.

    Ba, X. et al. Old drugs to treat resistant bugs: methicillin-resistant Staphylococcus aureus isolates with mecC are susceptible to a combination of penicillin and clavulanic acid. Antimicrob. Agents Chemother. 59, 7396–7404 (2015).

    CAS  Article  Google Scholar 

  17. 17.

    Weinstein, M. P. et al. M100 Performance Standards for Antimicrobial Susceptibility Testing 29th edn. (Clinical Laboratory Standards Institute, 2018).

  18. 18.

    Chambers, H. F. & Sachdeva, M. Binding of β-lactam antibiotics to penicillin-binding proteins in methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 161, 1170–1176 (1990).

    CAS  Article  Google Scholar 

  19. 19.

    Long, S. W. et al. PBP2a mutations causing high-level ceftaroline resistance in clinical methicillin-resistant Staphylococcus aureus isolates. Antimicrob. Agents Chemother. 58, 6668–6674 (2014).

    Article  Google Scholar 

  20. 20.

    Otero, L. H. et al. How allosteric control of Staphylococcus aureus penicillin-binding protein 2a enables methicillin resistance and physiological function. Proc. Natl Acad. Sci. USA 110, 16808–16813 (2013).

    Article  Google Scholar 

  21. 21.

    Harkins, C. P. et al. Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice. Genome Biol. 18, 130 (2017).

    Article  Google Scholar 

  22. 22.

    Gill, S. R. et al. Insights on evolution of virulence and resistance from the complete genome analysis of an early methicillin-resistant Staphylococcus aureus strain and a biofilm-producing methicillin-resistant Staphylococcus epidermidis strain. J. Bacteriol. 187, 2426–2438 (2005).

    CAS  Article  Google Scholar 

  23. 23.

    Loeffler, A. et al. First isolation of MRSA ST398 from UK animals: a new challenge for infection control teams? J. Hosp. Infect. 72, 269–271 (2009).

    CAS  Article  Google Scholar 

  24. 24.

    Paterson, G. K. et al. Incidence and characterisation of methicillin-resistant Staphylococcus aureus (MRSA) from nasal colonisation in participants attending a cattle veterinary conference in the UK. PLoS ONE 8, e68463 (2013).

    CAS  Article  Google Scholar 

  25. 25.

    Everitt, B. S. An introduction to finite mixture distributions. Stat. Methods Med. Res. 5, 107–127 (1996).

    CAS  Article  Google Scholar 

  26. 26.

    Hernandez-Garcia, J. et al. Patterns of antimicrobial resistance in Streptococcus suis isolates from pigs with or without streptococcal disease in England between 2009 and 2014. Vet. Microbiol. 207, 117–124 (2017).

    CAS  Article  Google Scholar 

  27. 27.

    Chen, F. J., Wang, C. H., Chen, C. Y., Hsu, Y. C. & Wang, K. T. Role of the mecA gene in oxacillin resistance in a Staphylococcus aureus clinical strain with a pvl-positive ST59 genetic background. Antimicrob. Agents Chemother. 58, 1047–1054 (2014).

    Article  Google Scholar 

  28. 28.

    Ender, M., McCallum, N. & Berger-Bachi, B. Impact of mecA promoter mutations on mecA expression and β-lactam resistance levels. Int. J. Med. Microbiol. 298, 607–617 (2008).

    CAS  Article  Google Scholar 

  29. 29.

    DANMAP (Statums Serum Institute, 2018); https://www.danmap.org/

  30. 30.

    Coll, F. et al. Longitudinal genomic surveillance of MRSA reveals extensive transmission in hospitals and the community. Sci. Transl. Med. 9, eaak9745 (2017).

    Article  Google Scholar 

  31. 31.

    Toleman, M. S. et al. Systematic surveillance detects multiple silent introductions and household transmission of methicillin-resistant Staphylococcus aureus USA300 in the east of England. J. Infect. Dis. 214, 447–453 (2016).

    Article  Google Scholar 

  32. 32.

    Jamrozy, D. M. et al. Pan-genomic perspective on the evolution of the Staphylococcus aureus USA300 epidemic. Microb. Genom. 2, e000058 (2016).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Uhlemann, A. C. et al. Molecular tracing of the emergence, diversification, and transmission of S. aureus sequence type 8 in a New York community. Proc. Natl Acad. Sci. USA 111, 6738–6743 (2014).

    CAS  Article  Google Scholar 

  34. 34.

    Hartman, B. J. & Tomasz, A. Expression of methicillin resistance in heterogeneous strains of Staphylococcus aureus. Antimicrob. Agents Chemother. 29, 85–92 (1986).

    CAS  Article  Google Scholar 

  35. 35.

    Larsen, A. R. et al. Two distinct clones of methicillin-resistant Staphylococcus aureus (MRSA) with the same USA300 pulsed-field gel electrophoresis profile: a potential pitfall for identification of USA300 community-associated MRSA. J. Clin. Microbiol. 47, 3765–3768 (2009).

    CAS  Article  Google Scholar 

  36. 36.

    Collins, J. et al. Offsetting virulence and antibiotic resistance costs by MRSA. ISME J. 4, 577–584 (2010).

    Article  Google Scholar 

  37. 37.

    Rudkin, J. K. et al. Methicillin resistance reduces the virulence of healthcare-associated methicillin-resistant Staphylococcus aureus by interfering with the agr quorum sensing system. J. Infect. Dis. 205, 798–806 (2012).

    CAS  Article  Google Scholar 

  38. 38.

    Pozzi, C. et al. Methicillin resistance alters the biofilm phenotype and attenuates virulence in Staphylococcus aureus device-associated infections. PLoS Pathog. 8, e1002626 (2012).

    CAS  Article  Google Scholar 

  39. 39.

    Pal, C., Papp, B. & Lazar, V. Collateral sensitivity of antibiotic-resistant microbes. Trends Microbiol. 23, 401–407 (2015).

    CAS  Article  Google Scholar 

  40. 40.

    BSAC Methods for Antimicrobial Susceptibility Testing Version 14 (British Society for Antimicrobial Chemotherapy, 2015).

  41. 41.

    Ersoy, S. C. et al. Correcting a fundamental flaw in the paradigm for antimicrobial susceptibility testing. EBioMedicine 20, 173–181 (2017).

    Article  Google Scholar 

  42. 42.

    Martin, C. et al. Comparison of concentrations of two doses of clavulanic acid (200 and 400 milligrams) administered with amoxicillin (2,000 milligrams) in tissues of patients undergoing colorectal surgery. Antimicrob. Agents Chemother. 39, 94–98 (1995).

    CAS  Article  Google Scholar 

  43. 43.

    Kahlmeter, G. The 2014 Garrod Lecture: EUCAST—are we heading towards international agreement? J. Antimicrob. Chemother. 70, 2427–2439 (2015).

    Article  Google Scholar 

  44. 44.

    Nicolas, M. H., Kitzis, M. D. & Karim, A. Stérilisation par 2 grammes d’Augmentin® des urines infectées à Staphylococcus aureus résistant à la méticilline. Med. Mal. Infect. 23, 82–94 (1993).

    Article  Google Scholar 

  45. 45.

    Franciolli, M., Bille, J., Glauser, M. P. & Moreillon, P. β-lactam resistance mechanisms of methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 163, 514–523 (1991).

    CAS  Article  Google Scholar 

  46. 46.

    Andreoni, M., Raillard, P., Concia, E. & Wang, Y. Sulbactam/ampicillin in the treatment of skin and soft-tissue infections due of methicillin-resistance staphylococci. A pilot study. Curr. Ther. Res. Clin. Exp. 50, 386–395 (1991).

    Google Scholar 

  47. 47.

    Nigo, M. et al. Ceftaroline-resistant, daptomycin-tolerant, and heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus causing infective endocarditis. Antimicrob. Agents Chemother. 61, e01235-16 (2017).

    Article  Google Scholar 

  48. 48.

    Steenbergen, J. N., Mohr, J. F. & Thorne, G. M. Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies. J. Antimicrob. Chemother. 64, 1130–1138 (2009).

    CAS  Article  Google Scholar 

  49. 49.

    Dilworth, T. J. et al. β-lactams enhance vancomycin activity against methicillin-resistant Staphylococcus aureus bacteremia compared to vancomycin alone. Antimicrob. Agents Chemother. 58, 102–109 (2014).

    Article  Google Scholar 

  50. 50.

    Reed, P. et al. Staphylococcus aureus survives with a minimal peptidoglycan synthesis machine but sacrifices virulence and antibiotic resistance. PLoS Pathog. 11, e1004891 (2015).

    Article  Google Scholar 

  51. 51.

    Andrews, J. M. Determination of minimum inhibitory concentrations. J. Antimicrob. Chemother. 48, 5–16 (2001).

    CAS  Article  Google Scholar 

  52. 52.

    Monk, I. R., Shah, I., Xu, M., Tan, M.-W. & Foster, T. J. Transforming the untransformable: application of direct transformation to manipulate genetically Staphylococcus aureus and Staphylococcus epidermidis. mBio 3, 11 (2012).

    Article  Google Scholar 

  53. 53.

    Corrigan, R. M. & Foster, T. J. An improved tetracycline-inducible expression vector for Staphylococcus aureus. Plasmid 61, 126–129 (2009).

    CAS  Article  Google Scholar 

  54. 54.

    Grilo, I. R., Ludovice, A. M., Tomasz, A., de Lencastre, H. & Sobral, R. G. The glucosaminidase domain of Atl—the major Staphylococcus aureus autolysin—has DNA-binding activity. MicrobiologyOpen 3, 247–256 (2014).

    CAS  Article  Google Scholar 

  55. 55.

    Zhao, G., Meier, T. I., Kahl, S. D., Gee, K. R. & Blaszczak, L. C. BOCILLIN FL, a sensitive and commercially available reagent for detection of penicillin-binding proteins. Antimicrob. Agents Chemother. 43, 1124–1128 (1999).

    CAS  Article  Google Scholar 

  56. 56.

    Kim, C. et al. Properties of a novel PBP2A protein homolog from Staphylococcus aureus strain LGA251 and its contribution to the β-lactam-resistant phenotype. J. Biol. Chem. 287, 36854–36863 (2012).

    CAS  Article  Google Scholar 

  57. 57.

    Bouley, R. et al. Discovery of antibiotic (E)-3-(3-carboxyphenyI)-2-(4-cyanostyryl)quinazolin-4(3H)-one. J. Am. Chem. Soc. 137, 1738–1741 (2015).

    CAS  Article  Google Scholar 

  58. 58.

    Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25, 402–408 (2001).

    CAS  Article  Google Scholar 

  59. 59.

    Desbois, A. P. & Coote, P. J. Wax moth larva (Galleria mellonella): an in vivo model for assessing the efficacy of antistaphylococcal agents. J. Antimicrob. Chemother. 66, 1785–1790 (2011).

    CAS  Article  Google Scholar 

  60. 60.

    Laabei, M. et al. Evolutionary trade-offs underlie the multi-faceted virulence of Staphylococcus aureus. PLoS Biol. 13, e1002229 (2015).

    Article  Google Scholar 

  61. 61.

    Ziebuhr, W. et al. Detection of the intercellular adhesion gene cluster (ica) and phase variation in Staphylococcus epidermidis blood culture strains and mucosal isolates. Infect. Immun. 65, 890–896 (1997).

  62. 62.

    Page, A. J. et al. Robust high-throughput prokaryote de novo assembly and improvement pipeline for Illumina data. Microb. Genom. 2, e000083 (2016).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Gladman, S. & Seemann, T. Velvet Optimiser: automate your Velvet assemblies (GitHub, 2008); https://github.com/tseemann/VelvetOptimiser

  64. 64.

    Zerbino, D. R. & Birney, E. Velvet: algorithms for de novo short read assembly using de Bruijn graphs. Genome Res. 18, 821–829 (2008).

    CAS  Article  Google Scholar 

  65. 65.

    Boetzer, M., Henkel, C. V., Jansen, H. J., Butler, D. & Pirovano, W. Scaffolding pre-assembled contigs using SSPACE. Bioinformatics 27, 578–579 (2011).

    CAS  Article  Google Scholar 

  66. 66.

    Boetzer, M. & Pirovano, W. Toward almost closed genomes with GapFiller. Genome Biol. 13, R56 (2012).

    Article  Google Scholar 

  67. 67.

    Edgar, R. C. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 32, 1792–1797 (2004).

    CAS  Article  Google Scholar 

  68. 68.

    Gouy, M., Guindon, S. & Gascuel, O. SeaView version 4: a multiplatform graphical user interface for sequence alignment and phylogenetic tree building. Mol. Biol. Evol. 27, 221–224 (2010).

    CAS  Article  Google Scholar 

  69. 69.

    Ambler, R. P. et al. A standard numbering scheme for the class A β-lactamases. Biochem. J. 276, 269–270 (1991).

    CAS  Article  Google Scholar 

  70. 70.

    Voladri, R. K. & Kernodle, D. S. Characterization of a chromosomal gene encoding type B β-lactamase in phage group II isolates of Staphylococcus aureus. Antimicrob. Agents Chemother. 42, 3163–3168 (1998).

    CAS  Article  Google Scholar 

  71. 71.

    Diep, B. A. et al. Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367, 731–739 (2006).

    CAS  Article  Google Scholar 

  72. 72.

    Croucher, N. J. et al. Rapid phylogenetic analysis of large samples of recombinant bacterial whole genome sequences using Gubbins. Nucleic Acids Res. 43, e15 (2015).

    Article  Google Scholar 

  73. 73.

    Stamatakis, A. RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30, 1312–1313 (2014).

    CAS  Article  Google Scholar 

  74. 74.

    Guindon, S. et al. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst. Biol. 59, 307–321 (2010).

    CAS  Article  Google Scholar 

  75. 75.

    Lim, D. & Strynadka, N. C. Structural basis for the β lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat. Struct. Biol. 9, 870–876 (2002).

    CAS  PubMed  Google Scholar 

  76. 76.

    Pettersen, E. F. et al. UCSF Chimera—a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank L. R. Hansen Kildevang and A. Medina for testing of the Danish isolates. We thank É. Brouillette and F. Malouin for providing isolates. This work was supported by Medical Research Council partnership grants (G1001787/1 and MR/N002660/1) held between the Department of Veterinary Medicine and School of Clinical Medicine at the University of Cambridge, the Moredun Research Institute and the Wellcome Sanger Institute. This publication presents independent research supported by the Health Innovation Challenge Fund (WT098600 and HICF-T5-342)—a parallel funding partnership between the Department of Health and Wellcome Trust. The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health or Wellcome Trust. E.M.H. is supported by a UK Research and Innovation Fellowship (MR/S00291X/1). F.C. is supported by the Wellcome Trust (201344/Z/16/Z). X.B. is supported by a UK–China AMR Partnership Grant (MR/P007201/1).

Author information

Affiliations

Authors

Contributions

E.M.H., X.B., S.J.P. and M.A.H. designed the study. X.B. performed the mecA deletion and complementation, expression analysis, and bocillin assays. X.B., B.B., N.G. and K.L.B. did the antimicrobial susceptibility testing. H.C. and R.C.M. ran the biofilm and toxicity assays. J.L. and A.R.L. determined the antimicrobial susceptibility testing of Danish isolates. O.R. determined the ECOFF. A.L. analysed the structure of PBP2a. E.M.H., X.B. and C.V.L. performed the infection and treatment experiments. I.R.G. and R.S. ran the bocillin binding assays. E.M.H., F.C., S.R. and D.J. performed the bioinformatics analysis of whole-genome sequence data. A.-C.U. and F.D.L. collected the USA300 isolates. N.G. wrote the bioinformatics scripts. C.U.K., G.K.P., M.T.G.H. and J.P. analysed and interpreted the data. E.M.H. coordinated the study and wrote the manuscript. S.J.P. and M.A.H. supervised and managed the study. All authors read, contributed to and approved the final manuscript.

Corresponding author

Correspondence to Ewan M. Harrison.

Ethics declarations

Competing interests

C.U.K. is a consultant for the World Health Organization Regional Office for Europe, QuantuMDx Group and Foundation for Innovative New Diagnostics, which involves work for Cepheid, Hain Lifescience and the World Health Organization. C.U.K. is an advisor to GenoScreen. The European Society of Mycobacteriology awarded C.U.K. the Gertrud Meissner Award, which is sponsored by Hain Lifescience. The Bill and Melinda Gates Foundation, Janssen Pharmaceutica and PerkinElmer covered C.U.K.’s travel and accommodation to enable presentations at meetings. The Global Alliance for TB Drug Development and Otsuka Novel Products have supplied C.U.K. with antibiotics for in vitro research. C.U.K. has collaborated with Illumina on a number of scientific projects. S.J.P. and J.P. are consultants to Next Gen Diagnostics. S.J.P. is a consultant to Specific Technologies. All other authors have no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–7, Tables 2 and 6–8, Supplementary Discussion, Supplementary References, and footnotes for Supplementary Tables 1 and 3–5.

Reporting Summary

Supplementary Table 1

Key features of 110 MRSA isolates screened for β-lactam resistance.

Supplementary Table 3

Key features of 298 MRSA isolates screened for penicillin–clavulanic acid susceptibility.

Supplementary Table 4

Key features of Danish clinical isolates screened for penicillin–clavulanic acid susceptibility.

Supplementary Table 5

Relevant characteristics of CC8 and USA300 included in Fig. 4b.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Harrison, E.M., Ba, X., Coll, F. et al. Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus. Nat Microbiol 4, 1680–1691 (2019). https://doi.org/10.1038/s41564-019-0471-0

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing