Bacterial cheating drives the population dynamics of cooperative antibiotic resistance plasmids

Abstract

Inactivation of β-lactam antibiotics by resistant bacteria is a 'cooperative' behavior that may allow sensitive bacteria to survive antibiotic treatment. However, the factors that determine the fraction of resistant cells in the bacterial population remain unclear, indicating a fundamental gap in our understanding of how antibiotic resistance evolves. Here, we experimentally track the spread of a plasmid that encodes a β-lactamase enzyme through the bacterial population. We find that independent of the initial fraction of resistant cells, the population settles to an equilibrium fraction proportional to the antibiotic concentration divided by the cell density. A simple model explains this behavior, successfully predicting a data collapse over two orders of magnitude in antibiotic concentration. This model also successfully predicts that adding a commonly used β-lactamase inhibitor will lead to the spread of resistance, highlighting the need to incorporate social dynamics into the study of antibiotic resistance.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 47

1. 1.

   Andersson DI (2006 ) The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 9: 461–465

   Not in our library10.1016/j.mib.2006.07.002

2. 2.

   Bonomo RA, Tolmasky ME (eds) (2007 ) Enzyme-Mediated Resistance to Antibiotics: Mechanisms, Dissemination, and Prospects for Inhibition 1st edn. Amer Society for Microbiology: Washington, DC,

   Not in our library

3. 3.

   Bouma JE, Lenski RE (1988 ) Evolution of a bacteria/plasmid association. Nature 335: 351–352

   Not in our library10.1038/335351a0

4. 4.

   Bret L, Chaibi EB, Chanal-Claris C, Sirot D, Labia R, Sirot J (1997 ) Inhibitor-resistant TEM (IRT) beta-lactamases with different substitutions at position 244. AntimicrobAgents Chemother 41: 2547–2549

   Not in our library10.1128/aac.41.11.2547

5. 5.

   Brook I (1984 ) The role of β-lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Clin Infect Dis 6: 601–607

   Not in our library10.1093/clinids/6.5.601

6. 6.

   Brook I (1989 ) Inoculum effect. Clin Infect Dis 11: 361–368

   Not in our library10.1093/clinids/11.3.361

7. 7.

   Brook I (2004 ) β-Lactamase-producing bacteria in mixed infections. Clin Microbiol Infect 10: 777–784

   Not in our library10.1111/j.1198-743x.2004.00962.x

8. 8.

   Bush K (1988 ) Beta-lactamase inhibitors from laboratory to clinic. Clin Microbiol Rev 1: 109–123

   Not in our library10.1128/cmr.1.1.109

9. 9.

   Celiker H, Gore J (2012 ) Competition between species can stabilize public-goods cooperation within a species. Mol Syst Biol 8: 621

   Not in our library10.1038/msb.2012.54

10. 10.

    Dahlberg C, Chao L (2003 ) Amelioration of the cost of conjugative plasmid carriage in Eschericha Coli K12. Genetics 165: 1641–1649

    Not in our library10.1093/genetics/165.4.1641

11. 11.

    Datta MS, Korolev KS, Cvijovic I, Dudley C, Gore J (2013 ) Range expansion promotes cooperation in an experimental microbial metapopulation. PNAS 110: 7354–7359

    Not in our library10.1073/pnas.1217517110

12. 12.

    Davies J (1994 ) Inactivation of antibiotics and the dissemination of resistance genes. Science 264: 375–382

    Not in our library10.1126/science.8153624

13. 13.

    Doebeli M, Hauert C (2005 ) Models of cooperation based on the Prisoner’s Dilemma and the Snowdrift game. Ecol Lett 8: 748–766

    Not in our library

14. 14.

    Drawz SM, Bonomo RA (2010 ) Three decades of β-lactamase inhibitors. Clin Microbiol Rev 23: 160–201

    Not in our library10.1128/cmr.00037-09

15. 15.
    Dynamic Behavior of Salmonella ‐Induced Membrane Tubules in Epithelial Cells · 2008

    No notice
16. 16.

    Dubus A, Wilkin JM, Raquet X, Normark S, Frère JM (1994 ) Catalytic mechanism of active-site serine beta-lactamases: role of the conserved hydroxy group of the Lys-Thr(Ser)-Gly triad. Biochem J 301: 485–494

    Not in our library10.1042/bj3010485

17. 17.

    Dugatkin LA, Perlin M, Atlas R (2003 ) The evolution of group-beneficial traits in the absence of between-group selection. J Theor Biol 220: 67–74

    Not in our library10.1006/jtbi.2003.3149

18. 18.

    Dugatkin LA, Perlin M, Lucas JS, Atlas R (2005 ) Group-beneficial traits, frequency-dependent selection and genotypic diversity: an antibiotic resistance paradigm. Proc Biol Sci 272: 79–83

    Not in our library10.1098/rspb.2004.2916

19. 19.

    Foulds G (1986 ) Pharmacokinetics of sulbactam/ampicillin in humans: a review. Clin Infect Dis 8: S503–S511

    Not in our library10.1093/clinids/8.supplement_5.503

20. 20.

    Garcia HG, Phillips R (2011 ) Quantitative dissection of the simple repression input–output function. PNAS 108: 12173–12178

    Not in our library10.1073/pnas.1015616108

21. 21.

    Goossens H, Ferech M, Vander Stichele R, Elseviers M (2005 ) Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 365: 579–587

    Not in our library10.1016/s0140-6736(05)17907-0

22. 22.

    Gore J, Youk H, van Oudenaarden A (2009 ) Snowdrift game dynamics and facultative cheating in yeast. Nature 459: 253–256

    Not in our library10.1038/nature07921

23. 23.

    Hackman AS, Wilkins TD (1975 ) In vivo protection of Fusobacterium necrophorum from penicillin by Bacteroides fragilis. Antimicrob Agents Chemother 7: 698–703

    Not in our library10.1128/aac.7.5.698

24. 24.

    Kerr B, Riley MA, Feldman MW, Bohannan BJM (2002 ) Local dispersal promotes biodiversity in a real-life game of rock-paper-scissors. Nature 418: 171–174

    Not in our library10.1038/nature00823

25. 25.

    Kitzis MD, Billot-Klein D, Goldstein FW, Williamson R, Nhieu GTV, Carlet J, Acar JF, Gutmann L (1988 ) Dissemination of the novel plasmid-mediated beta-lactamase CTX-1, which confers resistance to broad-spectrum cephalosporins, and its inhibition by beta-lactamase inhibitors. Antimicrob Agents Chemother 32: 9–14

    Not in our library10.1128/aac.32.1.9

26. 26.

    Lee HH, Molla MN, Cantor CR, Collins JJ (2010 ) Bacterial charity work leads to population-wide resistance. Nature 467: 82–85

    Not in our library10.1038/nature09354

27. 27.

    Lewis K (2007 ) Persister cells, dormancy and infectious disease. Nat Rev Microbiol 5: 48–56

    Not in our library10.1038/nrmicro1557

28. 28.

    Livermore DM (1995 ) Beta-lactamases in laboratory and clinical resistance. Clin Microbiol Rev 8: 557–584

    Not in our library10.1128/cmr.8.4.557

29. 29.

    Livermore DM, Moosdeen F, Lindridge MA, Kho P, Williams JD (1986 ) Behaviour of TEM-1 β-lactamase as a resistance mechanism to ampicillin, mezlocillin and azlocillin in Escherichia coli. J Antimicrob Chemother 17: 139–146

    Not in our library10.1093/jac/17.2.139

30. 30.

    Lutz R, Bujard H (1997 ) Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. Nucleic Acids Res 25: 1203–1210

    Not in our library10.1093/nar/25.6.1203

31. 31.

    May RM (1976 ) Simple mathematical models with very complicated dynamics. Nature 261: 459–467

    Not in our library10.1038/261459a0

32. 32.

    Narisawa N, Haruta S, Arai H, Ishii M, Igarashi Y (2008 ) Coexistence of antibiotic-producing and antibiotic-sensitive bacteria in biofilms is mediated by resistant bacteria. Appl Environ Microbiol 74: 3887–3894

    Not in our library10.1128/aem.02497-07

33. 33.

    Neu HC (1992 ) The crisis in antibiotic resistance. Science 257: 1064–1073

    Not in our library10.1126/science.257.5073.1064

34. 34.

    Nikaido H, Normark S (1987 ) Sensitivity of Escherichia coli to various β-lactams is determined by the interplay of outer membrane permeability and degradation by periplasmic β-lactamases: a quantitative predictive treatment. Mol Microbiol 1: 29–36

    Not in our library10.1111/j.1365-2958.1987.tb00523.x

35. 35.

    Nowak MA, Sigmund K (2004 ) Evolutionary dynamics of biological games. Science 303: 793–799

    Not in our library10.1126/science.1093411

36. 36.

    O’Connell HA, Kottkamp GS, Eppelbaum JL, Stubblefield BA, Gilbert SE, Gilbert ES (2006 ) Influences of biofilm structure and antibiotic resistance mechanisms on indirect pathogenicity in a model polymicrobial biofilm. Appl Environ Microbiol 72: 5013–5019

    Not in our library10.1128/aem.02474-05

37. 37.

    Palmer AC, Angelino E, Kishony R (2010 ) Chemical decay of an antibiotic inverts selection for resistance. Nat Chem Biol 6: 105–107

    Not in our library10.1038/nchembio.289

38. 38.

    Perlin MH, Clark DR, McKenzie C, Patel H, Jackson N, Kormanik C, Powell C, Bajorek A, Myers DA, Dugatkin LA, Atlas RM (2009 ) Protection of Salmonella by ampicillin-resistant Escherichia coli in the presence of otherwise lethal drug concentrations. Proc Biol Sci 276: 3759–3768

    Not in our library10.1098/rspb.2009.0997

39. 39.
    Feedback between Population and Evolutionary Dynamics Determines the Fate of Social Microbial Populations · 2013

    No notice
40. 40.

    Sykes RB, Matthew M (1976 ) The β-lactamases of Gram-negative bacteria and their rôle in resistance to β-lactam antibiotics. J Antimicrob Chemother 2: 115–157

    Not in our library10.1093/jac/2.2.115

Cited by papers we hold 10

• Ecology and evolution of antimicrobial resistance in bacterial communities · 2020
  No notice
• Pervasive and diverse collateral sensitivity profiles inform optimal strategies to limit antibiotic resistance · 2019
  No notice
• Selection for antimicrobial resistance is reduced when embedded in a natural microbial community · 2019
  No notice
• Novel Insights into Selection for Antibiotic Resistance in Complex Microbial Communities · 2018
  No notice
• Modifying and reacting to the environmental pH can drive bacterial interactions · 2018
  No notice
• Diverse genetic error modes constrain large-scale bio-based production · 2018
  No notice
• The Complex Relationship between Virulence and Antibiotic Resistance · 2017
  No notice
• Environmental and genetic modulation of the phenotypic expression of antibiotic resistance · 2017
  No notice
• Collective Resistance in Microbial Communities by Intracellular Antibiotic Deactivation · 2016
  No notice
• The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation · 2016
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.