Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Fosfomycin and Staphylococcus aureus: transcriptomic approach to assess effect on biofilm, and fate of unattached cells

The Journal of Antibiotics volume 73, pages 91–100 (2020)Cite this article

Subjects

Abstract

Interest has been rekindled in the old antibiotic fosfomycin, partly because of its ability to penetrate biofilm. Using a transcriptomic approach, we investigated the modifications induced by fosfomycin in sessile cells of a clinical Staphylococcus aureus isolated from a device-associated infection. Cells still able to form biofilm after 4 h of incubation in the presence of subinhibitory concentrations of fosfomycin and cells from 24-h-old biofilm later submitted to fosfomycin had 6.77% and 9.41%, respectively, of differentially expressed genes compared with their antibiotic-free control. Fosfomycin induced mostly downregulation of genes assigned to nucleotide, amino acid and carbohydrate transport, and metabolism. Adhesins and capsular biosynthesis proteins encoding genes were downregulated in fosfomycin-grown biofilm, whereas the murein hydrolase regulator lgrA and a d-lactate dehydrogenase-encoding gene were upregulated. In fosfomycin-treated biofilm, the expression of genes encoding adhesins, the cell wall biosynthesis protein ScdA, and to a lesser extent the fosfomycin target MurA was also decreased. Unattached cells surrounding fosfomycin-grown biofilm showed greater ability to form aggregates than their counterparts obtained without fosfomycin. Reducing their global metabolism and lowering cell wall turnover would allow some S. aureus cells to grow in biofilm despite fosfomycin stress while promoting hyperadherent phenotype in the vicinity of the fosfomycin-treated biofilm.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Del Pozo JL, Patel R. Infection associated with prosthetic joints. N Engl J Med. 2009;361:787–94.

    Article  Google Scholar 

  2. Lebeaux D, Ghigo J-M, Beloin C. Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics. Microbiol Mol Biol Rev. 2014;78:510–43.

    Article  CAS  Google Scholar 

  3. Cha J-O, Park Y-K, Lee YS, Chung GT. In vitro biofilm formation and bactericidal activities of methicillin-resistant Staphylococcus aureus clones prevalent in Korea. Diagn Microbiol Infect Dis. 2011;70:112–8.

    Article  CAS  Google Scholar 

  4. Marquès C, Tasse J, Pracros A, Collin V, Franceschi C, Laurent F, et al. Effects of antibiotics on biofilm and unattached cells of a clinical Staphylococcus aureus isolate from bone and joint infection. J Med Microbiol. 2015;64:1021–6.

    Article  Google Scholar 

  5. Siala W, Mingeot-Leclercq M-P, Tulkens PM, Hallin M, Denis O, Van Bambeke F. Comparison of the antibiotic activities of daptomycin, vancomycin, and the investigational fluoroquinolone delafloxacin against biofilms from Staphylococcus aureus clinical isolates. Antimicrob Agents Chemother. 2014;58:6385–97.

    Article  Google Scholar 

  6. Kaplan JB, Izano EA, Gopal P, Karwacki MT, Kim S, Bose JL, et al. Low levels of β-lactam antibiotics induce extracellular DNA release and biofilm formation in Staphylococcus aureus. mBio. 2012;3:e00198–112.

    Article  CAS  Google Scholar 

  7. Lázaro-Díez M, Remuzgo-Martínez S, Rodríguez-Mirones C, Acosta F, Icardo JM, Martínez-Martínez L, et al. Effects of subinhibitory concentrations of ceftaroline on methicillin-resistant Staphylococcus aureus (MRSA) biofilms. PLoS One. 2016;11:e0147569.

    Article  Google Scholar 

  8. Ng M, Epstein SB, Callahan MT, Piotrowski BO, Simon GL, Roberts AD, et al. Induction of MRSA biofilm by low-dose β-Lactam Antibiotics: specificity, prevalence and dose-response effects. Dose Response. 2014;12:152–61.

    Article  CAS  Google Scholar 

  9. Wang Q, Sun F-J, Liu Y, Xiong L-R, Xie L-L, Xia P-Y. Enhancement of biofilm formation by subinhibitory concentrations of macrolides in icaADBC-positive and -negative clinical isolates of Staphylococcus epidermidis. Antimicrob Agents Chemother. 2010;54:2707–11.

    Article  CAS  Google Scholar 

  10. Hengzhuang W, Wu H, Ciofu O, Song Z, Høiby N. In vivo pharmacokinetics/pharmacodynamics of colistin and imipenem in Pseudomonas aeruginosa biofilm infection. Antimicrob Agents Chemother. 2012;56:2683–90.

    Article  Google Scholar 

  11. Tang H-J, Chen C-C, Cheng K-C, Toh H-S, Su B-A, Chiang S-R, et al. In vitro efficacy of fosfomycin-containing regimens against methicillin-resistant Staphylococcus aureus in biofilms. J Antimicrob Chemother. 2012;67:944–50.

    Article  CAS  Google Scholar 

  12. Tang H-J, Chen C-C, Cheng K-C, Wu K-Y, Lin Y-C, Zhang C-C, et al. In vitro efficacies and resistance profiles of rifampin-based combination regimens for biofilm-embedded methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2013;57:5717–20.

    Article  CAS  Google Scholar 

  13. Barry AL, Brown SD. Antibacterial spectrum of fosfomycin trometamol. J Antimicrob Chemother. 1995;35:228–30.

    Article  CAS  Google Scholar 

  14. Pérez DS, Tapia MO, Soraci AL. Fosfomycin: uses and potentialities in veterinary medicine. Open Vet J. 2014;4:26–43.

    PubMed  PubMed Central  Google Scholar 

  15. Falagas ME, Kastoris AC, Karageorgopoulos DE, Rafailidis PI. Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies. Int J Antimicrob Agents. 2009;34:111–20.

    Article  CAS  Google Scholar 

  16. Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ. Fosfomycin. Clin Microbiol Rev. 2016;29:321–47.

    Article  CAS  Google Scholar 

  17. Neuner EA, Sekeres J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother. 2012;56:5744–8.

    Article  CAS  Google Scholar 

  18. Castañeda-García A, Blázquez J, Rodríguez-Rojas A. Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance. Antibiotics. 2013;2:217–36.

    Article  Google Scholar 

  19. Marquès C, Franceschi C, Collin V, Laurent F, Chatellier S, Forestier C. Genome sequence of a clinical Staphylococcus aureus strain from a prosthetic joint infection. Genome Announc. 2016;4:2.

  20. Utaida S, Dunman PM, Macapagal D, Murphy E, Projan SJ, Singh VK, et al. Genome-wide transcriptional profiling of the response of Staphylococcus aureus to cell-wall-active antibiotics reveals a cell-wall-stress stimulon. Microbiol Read Engl. 2003;149:2719–32.

    Article  CAS  Google Scholar 

  21. Kuroda M, Kuroda H, Oshima T, Takeuchi F, Mori H, Hiramatsu K. Two-component system VraSR positively modulates the regulation of cell-wall biosynthesis pathway in Staphylococcus aureus. Mol Microbiol. 2003;49:807–21.

    Article  CAS  Google Scholar 

  22. Dengler V, Meier P, Heusser R, Berger-Bächi B, McCallum N. Induction kinetics of the Staphylococcus aureus cell wall stress stimulon in response to different cell wall active antibiotics. BMC Microbiol. 2011;11:16.

    Article  CAS  Google Scholar 

  23. Shen F, Tang X, Wang Y, Yang Z, Shi X, Wang C, et al. Phenotype and expression profile analysis of Staphylococcus aureus biofilms and planktonic cells in response to licochalcone A. Appl Microbiol Biotechnol. 2015;99:359–73.

    Article  CAS  Google Scholar 

  24. Groicher KH, Firek BA, Fujimoto DF, Bayles KW. The Staphylococcus aureus lrgAB operon modulates murein hydrolase activity and penicillin tolerance. J Bacteriol. 2000;182:1794–801.

    Article  CAS  Google Scholar 

  25. Petek M, Baebler S, Kuzman D, Rotter A, Podlesek Z, Gruden K, et al. Revealing fosfomycin primary effect on Staphylococcus aureus transcriptome: modulation of cell envelope biosynthesis and phosphoenolpyruvate induced starvation. BMC Microbiol. 2010;10:159.

    Article  Google Scholar 

  26. Qin N, Tan X, Jiao Y, Liu L, Zhao W, Yang S, et al. RNA-Seq-based transcriptome analysis of methicillin-resistant Staphylococcus aureus biofilm inhibition by ursolic acid and resveratrol. Sci Rep. 2014;4:5467.

    Article  CAS  Google Scholar 

  27. Coldren FM, Palavecino EL, Levi-Polyachenko NH, Wagner WD, Smith TL, Smith BP, et al. Encapsulated Staphylococcus aureus strains vary in adhesiveness assessed by atomic force microscopy. J Biomed Mater Res A. 2009;89:402–10.

    Article  Google Scholar 

  28. Dörries K, Schlueter R, Lalka M. Impact of antibiotics with various target sites on the metabolome of Staphylococcus aureus. Antimicrob Agents Chemother. 2014;58:7151–63.

    Article  Google Scholar 

  29. Xu Y, Maltesen RG, Larsen LH, Schønheyder HC, Le VQ, Nielsen JL, et al. In vivo gene expression in a Staphylococcus aureus prosthetic joint infection characterized by RNA sequencing and metabolomics: a pilot study. BMC Microbiol. 2016;16:80.

    Article  Google Scholar 

Download references

Acknowledgements

CIFRE fellowship from bioMérieux and the Association Nationale de la Recherche et de la Technologie (ANRT) for CM is gratefully acknowledged. We thank Ophélie Chapeira, GenoScreen—Lille, for her help in RNA-seq data analysis. We would like to thank Anne Pracros for her technical help, Damien Balestrino and Cyril Guilhen for their helpful advice in statistical analysis.

Author information

Authors and Affiliations

  1. bioMérieux SA, 38390, La Balme les Grottes, France

    Claire Marquès, Valérie Collin, Christine Franceschi & Sonia Chatellier

  2. Laboratoire des Microorganismes, Génome et Environnement, UMR CNRS 6023—Université Clermont Auvergne, 63000, Clermont-Ferrand, France

    Claire Marquès, Nicolas Charbonnel & Christiane Forestier

Authors
  1. Claire Marquès
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valérie Collin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Franceschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicolas Charbonnel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sonia Chatellier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christiane Forestier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christiane Forestier.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marquès, C., Collin, V., Franceschi, C. et al. Fosfomycin and Staphylococcus aureus: transcriptomic approach to assess effect on biofilm, and fate of unattached cells. J Antibiot 73, 91–100 (2020). https://doi.org/10.1038/s41429-019-0256-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-019-0256-y

Search

Advanced search

Quick links