Review Article | Published:

Antibiotic resistance and its cost: is it possible to reverse resistance?

Nature Reviews Microbiology volume 8, pages 260271 (2010) | Download Citation


Most antibiotic resistance mechanisms are associated with a fitness cost that is typically observed as a reduced bacterial growth rate. The magnitude of this cost is the main biological parameter that influences the rate of development of resistance, the stability of the resistance and the rate at which the resistance might decrease if antibiotic use were reduced. These findings suggest that the fitness costs of resistance will allow susceptible bacteria to outcompete resistant bacteria if the selective pressure from antibiotics is reduced. Unfortunately, the available data suggest that the rate of reversibility will be slow at the community level. Here, we review the factors that influence the fitness costs of antibiotic resistance, the ways by which bacteria can reduce these costs and the possibility of exploiting them.

Key points

  • Most antibiotic resistance mechanisms are associated with a fitness cost, which is a key biological parameter that influences the development of resistance.

  • The fitness cost is the main driver of resistance reversibility at the community level. Thus, the bigger the fitness cost, the faster the reversibility.

  • The rate of reversibility is expected to be slow at the community level because of compensatory evolution, cost-free mutations and genetic co-selection.

  • Knowledge about fitness costs and compensatory mutations can be used to reduce the likelihood of bacteria developing resistance, by enabling us to choose antibiotics for which the resistance mechanism confers a high fitness cost and the rate and extent of compensation mutations are low.

  • It may be possible to exploit the detailed knowledge of the physiological basis of fitness costs in the choice and design of novel therapies that could target the physiological weaknesses associated with a particular resistance mechanism.

  • An understanding of fitness costs and compensatory evolution should allow us to make better quantitative predictions about the rate and trajectory of the evolution of resistance to new and old drugs.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Antimicrobial resistance: priorities for action. J. Antimicrob. Chemother.49, 585–586 (2002).

  2. 2.

    & Infections caused by Gram-positive bacteria: a review of the global challenge. J. Infect.59 (Suppl. 1), S4–S16 (2009).

  3. 3.

    , , , & Initial drug resistance and tuberculosis treatment outcomes: systematic review and meta-analysis. Ann. Intern. Med.149, 123–134 (2008).

  4. 4.

    Contemporary management of uncomplicated urinary tract infections. Drugs68, 1169–1205 (2008).

  5. 5.

    et al. The population genetics of antibiotic resistance. Clin. Infect. Dis.24 (Suppl. 1), S9–S16 (1997).

  6. 6.

    & The biological cost of antibiotic resistance. Curr. Opin. Microbiol.2, 489–493 (1999).

  7. 7.

    Models for the spread of resistant pathogens. Neth. J. Med.60, 58–66 (2002).

  8. 8.

    Multidrug resistance in bacteria. Annu. Rev. Biochem.78, 119–146 (2009).

  9. 9.

    & Gene amplification and adaptive evolution in bacteria. Annu. Rev. Genet.43, 167–195 (2009).

  10. 10.

    & Bacterial gene amplification: implications for the evolution of antibiotic resistance. Nature Rev. Microbiol.7, 578–588 (2009).

  11. 11.

    & Quinolone resistance due to reduced target enzyme expression. J. Bacteriol.185, 6883–6892 (2003).

  12. 12.

    et al. Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nature Med.12, 83–88 (2006).

  13. 13.

    & Efflux-mediated drug resistance in bacteria: an update. Drugs69, 1555–1623 (2009).

  14. 14.

    Antibiotic resistance genes from the environment: a perspective through newly identified antibiotic resistance mechanisms in the clinical setting. Clin. Microbiol. Infect.15 (Suppl. 1), 20–25 (2009).

  15. 15.

    , & Predicting antibiotic resistance. Nature Rev. Microbiol.5, 958–965 (2007).

  16. 16.

    et al. Effect of macrolide consumption on erythromycin resistance in Streptococcus pyogenes in Finland in 1997–2001Clin. Infect. Dis.38, 1251–1256 (2004).

  17. 17.

    , , , & Association between antimicrobial consumption and resistance in Escherichia coli. Antimicrob. Agents Chemother.53, 912–917 (2009).

  18. 18.

    , & Functional characterization of the antibiotic resistance reservoir in the human microflora. Science325, 1128–1131 (2009).

  19. 19.

    & Amelioration of the cost of conjugative plasmid carriage in Eschericha coli K12. Genetics165, 1641–1649 (2003). This article shows that plasmids carrying antibiotic resistance genes impose fitness costs on their bacterial hosts but that these costs can quickly be ameliorated by mutations on either the plasmid or the chromosome.

  20. 20.

    & Evolution of a bacteria/plasmid association. Nature335, 351–352 (1988).

  21. 21.

    , , & Enhancement of host fitness by the sul2-coding plasmid p9123 in the absence of selective pressure. J. Antimicrob. Chemother.53, 958–963 (2004).

  22. 22.

    Antibiotic resistance: counting the cost. Curr. Biol.6, 1219–1221 (1996).

  23. 23.

    Minimizing potential resistance: a population dynamics view. Clin. Infect. Dis.33, S161–S169 (2001).

  24. 24.

    et al. Combining mathematical models and statistical methods to understand and predict the dynamics of antibiotic-sensitive mutants in a population of resistant bacteria during experimental evolution. Genetics168, 1131–1144 (2004).

  25. 25.

    et al. Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proc. Natl Acad. Sci. USA98, 14607–14612 (2001).

  26. 26.

    et al. Comparison of fitness of two isolates of Mycobacterium tuberculosis, one of which had developed multi-drug resistance during the course of treatment. J. Infect.41, 184–187 (2000).

  27. 27.

    , , , & Growth competition of macrolide-resistant and -susceptible Helicobacter pylori strains. Microbiol. Immunol.48, 977–980 (2004).

  28. 28.

    , , , & Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science287, 1479–1482 (2000). This work finds that different fitness-compensating mutations are selected depending on whether the bacteria evolve in animal models or in laboratory medium.

  29. 29.

    , & Virulence of antibiotic-resistant Salmonella typhimurium. Proc. Natl Acad. Sci. USA95, 3949–3953 (1998). This study shows that resistance mutations to different classes of antibiotic strongly reduce bacterial virulence but that second-site compensatory mutations can be selected that restore virulence without the loss of antibiotic resistance.

  30. 30.

    et al. Fitness cost of chromosomal drug resistance-conferring mutations. Antimicrob. Agents Chemother. 46, 1204–1211 (2002). A demonstration that chromosomal drug resistance mutations with little or no cost in vitro are preferentially found in clinical isolates of mycobacteria, arguing that decreased levels of antibiotic consumption will not result in a decline in the frequency of resistant mutants.

  31. 31.

    , & The fitness cost of Streptomycin resistance depends on rpsL mutation, carbon source and RpoS (σS). Genetics183, 539–546 (2009).

  32. 32.

    , , & Fitness cost of SCCmec and methicillin resistance levels in Staphylococcus aureus. Antimicrob. Agents Chemother.48, 2295–2297 (2004).

  33. 33.

    , , , & Analysis of mupirocin resistance and fitness in Staphylococcus aureus by molecular genetic and structural modeling techniques. Antimicrob. Agents Chemother.48, 4366–4376 (2004).

  34. 34.

    et al. Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure. Proc. Natl Acad. Sci. USA102, 541–546 (2005). In this article, the authors make the surprising observation that fluoroquinolone-resistant C. jejuni isolates with a mutation in gyrA outcompete clonally related fluoroquinolone-sensitive C. jejuni in the absence of antibiotic selection pressure in vivo (in the chicken). This indicates that the single point mutation not only confers a high-level resistance to fluoroquinolones but also modulates the in vivo fitness of C. jejuni.

  35. 35.

    , , , & Stability, persistence, and evolution of plasmid-encoded VanA glycopeptide resistance in enterococci in the absence of antibiotic selection in vitro and in gnotobiotic mice. Microb. Drug Resist.8, 161–170 (2002).

  36. 36.

    & Effects of segregation and selection on instability of plasmid pACYC184 in Escherichia coli B. J. Bacteriol.169, 5314–5316 (1987).

  37. 37.

    & Bacterial fitness and plasmid loss: the importance of culture conditions and plasmid size. Can. J. Microbiol.44, 351–355 (1998).

  38. 38.

    , , , & Biological cost of AmpC production for Salmonella enterica serotype Typhimurium. Antimicrob. Agents Chemother.44, 3137–3143 (2000).

  39. 39.

    , , & Biological cost and compensatory evolution in fusidic acid-resistant Staphylococcus aureus. Mol. Microbiol.40, 433–439 (2001). Here, the authors provide evidence that secondary mutations that compensate the biological fitness costs of antibiotic resistance arise in nature and may contribute to the stabilization of resistance in a bacterial population.

  40. 40.

    , , & Fusidic acid-resistant EF-G perturbs the accumulation of ppGpp. Mol. Microbiol.37, 98–107 (2000).

  41. 41.

    et al. Fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium with low fitness in vivo are defective in RpoS induction. Antimicrob. Agents Chemother.47, 3743–3749 (2003).

  42. 42.

    , & Fusidic acid-resistant mutants of Salmonella enterica serovar Typhimurium have low levels of heme and a reduced rate of respiration and are sensitive to oxidative stress. Antimicrob. Agents Chemother.48, 3877–3883 (2004).

  43. 43.

    & Hyper-susceptibility of a fusidic acid-resistant mutant of Salmonella to different classes of antibiotics. FEMS Microbiol. Lett.247, 215–220 (2005).

  44. 44.

    , , & Rifampicin resistance and its fitness cost in Enterococcus faecium. J. Antimicrob. Chemother.53, 203–207 (2004).

  45. 45.

    , , & Molecular genetic and structural modeling studies of Staphylococcus aureus RNA polymerase and the fitness of rifampin resistance genotypes in relation to clinical prevalence. Antimicrob. Agents Chemother.50, 298–309 (2006).

  46. 46.

    Compensatory evolution in rifampin-resistant Escherichia coli. Genetics156, 1471–1481 (2000).

  47. 47.

    , , , & Monitoring in vivo fitness of rifampicin-resistant Staphylococcus aureus mutants in a mouse biofilm infection model. J. Antimicrob. Chemother.55, 528–534 (2005).

  48. 48.

    et al. Stress-induced mutagenesis in bacteria. Science300, 1404–1409 (2003).

  49. 49.

    , & Accumulation of mutants in “aging” bacterial colonies is due to growth under selection, not stress-induced mutagenesis. Proc. Natl Acad. Sci. USA105, 11863–11868 (2008). This work finds that most rifampicin resistance mutations increase bacterial fitness in the environment of an ageing colony, showing that environment is a critically important determinant of relative fitness.

  50. 50.

    , & in Escherichia coli and Salmonella: Cellular and Molecular Biology (eds Neidhardt, F. C. et al.) 979–1004 (American Society for Microbiology, Washington DC, 1996).

  51. 51.

    & Suppression of rpsL phenotypes by tuf mutations reveals a unique relationship between translation elongation and growth rate. Mol. Microbiol.7, 275–284 (1993).

  52. 52.

    et al. Assessment of the fitness impacts on Escherichia coli of acquisition of antibiotic resistance genes encoded by different types of genetic element. J. Antimicrob. Chemother.56, 544–551 (2005).

  53. 53.

    , , & Fitness of antibiotic-resistant microorganisms and compensatory mutations. Nature Med.4, 1343–1344 (1998).

  54. 54.

    , & Glycopeptide resistance in enterococci. Trends Microbiol.4, 401–407 (1996).

  55. 55.

    et al. Molecular basis for vancomycin resistance in Enterococcus faecium BM4147: biosynthesis of a depsipeptide peptidoglycan precursor by vancomycin resistance proteins VanH and VanA. Biochemistry30, 10408–10415 (1991).

  56. 56.

    , & The VanS-VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM4147. J. Bacteriol.174, 2582–2591 (1992).

  57. 57.

    , & Fitness cost of VanA-type vancomycin resistance in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother.53, 2354–2359 (2009). In this important paper, the authors demonstrate that the fitness cost of the VanA-type glycopeptide resistance cassettes that are carried by clinical methicillin-resistant S. aureus isolates is very high when induced by the presence of the antibiotic but very low in the absence of induction.

  58. 58.

    , , , & Biological cost of single and multiple norfloxacin resistance mutations in Escherichia coli implicated in urinary tract infections. Antimicrob. Agents Chemother.49, 2343–2351 (2005).

  59. 59.

    , Karlsson, Å. & Mutation rate and evolution of fluoroquinolone resistance in Escherichia coli isolates from patients with urinary tract infections. Antimicrob. Agents Chemother.47, 3222–3232 (2003).

  60. 60.

    , & Quinolone resistance from a transferable plasmid. Lancet351, 797–799 (1998).

  61. 61.

    , & The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect. Dis.6, 629–640 (2006).

  62. 62.

    , & Interplay in the selection of fluoroquinolone resistance and bacterial fitness. PLoS Pathog.5, e1000541 (2009). These results reveal that the acquisition of an additional fluoroquinolone resistance mutation can not only increase drug resistance (as expected) but also significantly increase bacterial fitness. Thus, Darwinian selection for improved fitness can select for increased drug resistance even in the absence of the drug.

  63. 63.

    , & Analysis of rpoB and pncA mutations in the published literature: an insight into the role of oxidative stress in Mycobacterium tuberculosis evolution?J. Antimicrob. Chemother.55, 674–679 (2005).

  64. 64.

    , & Genetic and phenotypic identification of fusidic acid-resistant mutants with the small colony-variant phenotype in Staphylococcus aureus. Antimicrob. Agents Chemother.51, 4438–4446 (2007).

  65. 65.

    & Molecular basis of fusB-mediated resistance to fusidic acid in Staphylococcus aureus. Mol. Microbiol.59, 664–676 (2006).

  66. 66.

    , , , & Characterization of the epidemic European fusidic acid-resistant impetigo clone of Staphylococcus aureus. J. Clin. Microbiol.45, 1505–1510 (2007).

  67. 67.

    , , , & Genetic basis of resistance to fusidic acid in staphylococci. Antimicrob. Agents Chemother.51, 1737–1740 (2007).

  68. 68.

    , & Genetic determinants of resistance to fusidic acid among clinical bacteremia isolates of Staphylococcus aureus. Antimicrob. Agents Chemother.53, 2059–2065 (2009).

  69. 69.

    et al. Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus. Antimicrob. Agents Chemother.52, 4017–4022 (2008).

  70. 70.

    et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nature Rev. Microbiol.4, 295–305 (2006).

  71. 71.

    , & The effect of drug resistance on the fitness of Mycobacterium tuberculosis. Lancet Infect. Dis.3, 13–21 (2003).

  72. 72.

    , & Effect of inhA and katG on isoniazid resistance and virulence of Mycobacterium bovis. Mol. Microbiol.15, 1009–1015 (1995).

  73. 73.

    , , , & Expression of katG in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs. J. Infect. Dis.177, 1030–1035 (1998).

  74. 74.

    , & Effect of katG mutations on the virulence of Mycobacterium tuberculosis and the implication for transmission in humans. Infect. Immun.70, 4955–4960 (2002).

  75. 75.

    , & Isoniazid resistance and the future of drug-resistant tuberculosis. Microb. Drug Resist.10, 280–285 (2004).

  76. 76.

    β-Lactamase induction in Gram-negative bacteria is intimately linked to peptidoglycan recycling. Microb. Drug Resist.1, 111–114 (1995).

  77. 77.

    , , , & Bacterial cell wall recycling provides cytosolic muropeptides as effectors for β-lactamase induction. EMBO J.13, 4684–4694 (1994).

  78. 78.

    , & Cytosolic intermediates for cell wall biosynthesis and degradation control inducible β-lactam resistance in gram-negative bacteria. Cell88, 823–832 (1997).

  79. 79.

    et al. Coordinate regulation of beta-lactamase induction and peptidoglycan composition by the amp operon. Science251, 201–204 (1991).

  80. 80.

    , , , & Components of the peptidoglycan-recycling pathway modulate invasion and intracellular survival of Salmonella enterica serovar Typhimurium. Cell. Microbiol.7, 147–155 (2005).

  81. 81.

    & Caenorhabditis elegans: a model genetic host to study Pseudomonas aeruginosa pathogenesis. Curr. Opin. Microbiol.3, 29–34 (2000).

  82. 82.

    et al. Fitness of in vitro selected Pseudomonas aeruginosa nalB and nfxB multidrug resistant mutants. J. Antimicrob. Chemother.50, 657–664 (2002).

  83. 83.

    , & Infectious disease dynamics: what characterizes a successful invader?Philos. Trans. R. Soc. Lond. B Biol. Sci.356, 901–910 (2001).

  84. 84.

    , , , & Effect of drug resistance on the generation of secondary cases of tuberculosis. J. Infect. Dis.188, 1878–1884 (2003).

  85. 85.

    , & Drug resistance and fitness in Mycobacterium tuberculosis infection. J. Infect. Dis.191, 823–824 (2005).

  86. 86.

    , , & Superspreading and the effect of individual variation on disease emergence. Nature438, 355–359 (2005).

  87. 87.

    , , , & The epidemiological fitness cost of drug resistance in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA106, 14711–14715 (2009).

  88. 88.

    , , & Compensatory adaptation to the deleterious effect of antibiotic resistance in Salmonella typhimurium. Mol. Microbiol.46, 355–366 (2002).

  89. 89.

    , & Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. Genetics154, 985–997 (2000). Here, the authors use modelling to show that the trajectory of the adaptive evolution of low-fitness antibiotic-resistant bacteria will be strongly influenced by the relative rates of different mutations (reversion and compensatory mutations) and the population bottlenecks that these bacteria experience.

  90. 90.

    , & The role of compensatory mutations in the emergence of drug resistance. PLoS Comput. Biol.2, e137 (2006).

  91. 91.

    , , & Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium. Mol. Microbiol.31, 53–58 (1999).

  92. 92.

    , , & The dynamic structure of EF-G studied by fusidic acid resistance and internal revertants. J. Mol. Biol.258, 420–432 (1996).

  93. 93.

    et al. Reversion to susceptibility in a linezolid-resistant clinical isolate of Staphylococcus aureus. J. Antimicrob. Chemother.54, 818–820 (2004).

  94. 94.

    et al. Linezolid resistance in sequential Staphylococcus aureus isolates associated with a T2500A mutation in the 23S rRNA gene and loss of a single copy of rRNA. J. Infect. Dis.190, 311–317 (2004).

  95. 95.

    , , & Heterogeneous macrolide resistance and gene conversion in the pneumococcus. Antimicrob. Agents Chemother.50, 359–361 (2006).

  96. 96.

    et al. Reducing the fitness cost of antibiotic resistance by amplification of initiator tRNA genes. Proc. Natl Acad. Sci. USA103, 6976–6981 (2006). An important paper showing that amplification of an unrelated wild-type gene can restore growth fitness to an antibiotic-resistant mutant.

  97. 97.

    , , & Fitness costs of fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother.51, 412–416 (2007).

  98. 98.

    , , & Multiple drug-resistant Mycobacterium tuberculosis: evidence for changing fitness following passage through human hosts. Microb. Drug Resist.8, 273–279 (2002).

  99. 99.

    et al. Effects of overexpression of the alkyl hydroperoxide reductase AhpC on the virulence and isoniazid resistance of Mycobacterium tuberculosis. Infect. Immun.65, 1395–1401 (1997).

  100. 100.

    et al. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science312, 1944–1946 (2006).

  101. 101.

    et al. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science272, 1641–1643 (1996).

  102. 102.

    , & The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. Proc. Natl Acad. Sci. USA97, 1938–1943 (2000). This article describes the mathematical modelling that is used to propose practical measures to control or reduce the prevalence of antibiotic-resistant bacteria in hospital settings. It also discusses why it will be easier to control resistance in hospitals that in the community.

  103. 103.

    , & Understanding the spread of antibiotic resistant pathogens in hospitals: mathematical models as tools for control. Clin. Infect. Dis.33, 1739–1746 (2001).

  104. 104.

    & Studies of antibiotic resistance within the patient, hospitals and the community using simple mathematical models. Philos. Trans. R. Soc. Lond. B Biol. Sci.354, 721–738 (1999).

  105. 105.

    et al. Modelling the impact of antibiotic use and infection control practices on the incidence of hospital-acquired methicillin-resistant Staphylococcus aureus: a time-series analysis. J. Antimicrob. Chemother.62, 593–600 (2008).

  106. 106.

    et al. Impact of infection control interventions and antibiotic use on hospital MRSA: a multivariate interrupted time-series analysis. Int. J. Antimicrob. Agents30, 169–176 (2007).

  107. 107.

    Minimizing antimicrobial resistance in hospital bacteria: can switching or cycling drugs help?Infect. Control7, 573–576 (1986).

  108. 108.

    , , , & Persistence of resistant Staphylococcus epidermidis after single course of clarithromycin. Emerg. Infect. Dis.11, 1389–1393 (2005).

  109. 109.

    , , , & Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori. Ann. Intern. Med.139, 483–487 (2003). This article shows that an antibiotic treatment that successfully eradicates H. pylori in patients also selects for resistant entercocci that persist in the patients for up to 3 years without any further selection.

  110. 110.

    , & Effect of antimicrobial agents on the ecological balance of human microflora. Lancet Infect. Dis.1, 101–114 (2001).

  111. 111.

    et al. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N. Engl. J. Med.337, 441–446 (1997).

  112. 112.

    Effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci. Microb. Drug Resist.3, 117–123 (1997).

  113. 113.

    et al. Erythromycin resistance genes in group A streptococci in Finland. Antimicrob. Agents Chemother.43, 48–52 (1999).

  114. 114.

    et al. Clonal spread of resistant pneumococci despite diminished antimicrobial use. Microb. Drug Resist.8, 187–192 (2002).

  115. 115.

    , , , & Vancomycin-resistant enterococci in intensive-care hospital settings: transmission dynamics, persistence, and the impact of infection control programs. Proc. Natl Acad. Sci. USA96, 6908–6913 (1999).

  116. 116.

    , , & Persistence of sulphonamide resistance in Escherichia coli in the UK despite national prescribing restriction. Lancet357, 1325–1328 (2001). In this article, the authors show that reduced prescription of sulphonamides in the United Kingdom did not reduce resistance within a period of years, probably because of genetic linkage to other resistance determinants that continued to be under selection.

  117. 117.

    , , & Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man. J. Antimicrob. Chemother.56, 962–964 (2005).

  118. 118.

    et al. Little evidence for reversibility of trimethoprim resistance after a drastic reduction in trimethoprim use. J. Antimicrob. Chemother.65, 350–360 (2010). A key prospective intervention study in which trimethoprim consumption in a Swedish county was reduced by 85% for a period of 2 years. The authors conclude that reduced antibiotic consumption is unlikely to significantly reduce resistance levels in the community.

  119. 119.

    Quantifying fitness and gene stability in microorganisms. Biotechnology15, 173–192 (1991).

  120. 120.

    , & Mini-Tn7 transposons for site-specific tagging of bacteria with fluorescent proteins. Environ. Microbiol.6, 726–732 (2004).

  121. 121.

    et al. Noninvasive monitoring of pneumococcal meningitis and evaluation of treatment efficacy in an experimental mouse model. Mol. Imaging4, 137–142 (2005).

  122. 122.

    et al. Noninvasive biophotonic imaging for monitoring of catheter-associated urinary tract infections and therapy in mice. Infect. Immun.73, 3878–3887 (2005).

  123. 123.

    et al. Real-time in vivo bioluminescent imaging for evaluating the efficacy of antibiotics in a rat Staphylococcus aureus endocarditis model. Antimicrob. Agents Chemother.49, 380–387 (2005).

  124. 124.

    , , , & Fitness cost of fluoroquinolone resistance in Salmonella enterica serovar Typhimurium. J. Med. Microbiol.52, 697–703 (2003).

  125. 125.

    , & Multiple mechanisms to ameliorate the fitness burden of mupirocin resistance in Salmonella typhimurium. Mol. Microbiol.64, 1038–1048 (2007).

  126. 126.

    , & Adaptation to the fitness costs of antibiotic resistance in Escherichia coli. Proc. Biol. Sci.264, 1287–1291 (1997).

  127. 127.

    & Reducing antibiotic resistance. Nature381, 120–121 (1996). This is pioneering work demonstrating that the initially high cost of chromosomal streptomycin resistance mutations is rapidly compensated for in the absence of drug selection without a clinically significant reduction in the level of streptomycin resistance. The results argue that prudent antibiotic use alone may not be sufficient to reduce the prevalence of antibiotic resistance.

  128. 128.

    , , , & Biological costs and mechanisms of fosfomycin resistance in Escherichia coli. Antimicrob. Agents Chemother.47, 2850–2858 (2003).

  129. 129.

    , , & Effect of rpoB mutations conferring rifampin resistance on fitness of Mycobacterium tuberculosis. Antimicrob. Agents Chemother.48, 1289–1294 (2004).

  130. 130.

    , & Physiological cost of rifampin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrob. Agents Chemother.43, 1866–1869 (1999).

  131. 131.

    , , & Molecular analysis of fusidic acid resistance in Staphylococcus aureus. Mol. Microbiol.47, 463–469 (2003).

  132. 132.

    , , & Compensatory adaptation to the loss of biological fitness associated with acquisition of fusidic acid resistance in Staphylococcus aureus. Antimicrob. Agents Chemother.49, 1426–1431 (2005).

  133. 133.

    et al. Biological cost of rifampin resistance from the perspective of Staphylococcus aureus. Antimicrob. Agents Chemother.46, 3381–3385 (2002).

  134. 134.

    , & The isoleucyl-tRNA synthetase mutation V588F conferring mupirocin resistance in glycopeptide-intermediate Staphylococcus aureus is not associated with a significant fitness burden. J. Antimicrob. Chemother.53, 102–104 (2004).

  135. 135.

    , & Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on the skin of human volunteers. J. Antimicrob. Chemother.52, 258–263 (2003).

  136. 136.

    , , , & Relative fitness of fluoroquinolone-resistant Streptococcus pneumoniae. Emerg. Infect. Dis.11, 814–820 (2005).

  137. 137.

    & Fitness cost due to mutations in the 16S rRNA associated with spectinomycin resistance in Chlamydia psittaci 6BC. Antimicrob. Agents Chemother.49, 4455–4464 (2005).

  138. 138.

    , , & Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa. J. Antimicrob. Chemother.55, 22–30 (2005).

  139. 139.

    , , & Survival of rifampin-resistant mutants of Pseudomonas fluorescens and Pseudomonas putida in soil systems. Appl. Environ. Microbiol.54, 2432–2438 (1988).

  140. 140.

    & Fitness costs associated with class IIa bacteriocin resistance in Listeria monocytogenes B73. Lett. Appl. Microbiol.26, 5–8 (1998).

  141. 141.

    & Adaptation to sulfonamide resistance in Neisseria meningitidis may have required compensatory changes to retain enzyme function: kinetic analysis of dihydropteroate synthases from N. meningitidis expressed in a knockout mutant of Escherichia coli. J. Bacteriol.179, 831–837 (1997).

Download references


This work was supported by the Swedish Research Council, the European Union 5th, 6th and 7th Framework Programmes and the Swedish Agency for Innovations Systems (VINNOVA).

Author information


  1. Department of Medical Biochemistry and Microbiology, Uppsala University, BOX 582, SE-751 23, Uppsala, Sweden.

    • Dan I. Andersson
  2. Department of Cell and Molecular Biology, Uppsala University, BOX 596, SE-751 24, Uppsala, Sweden.

    • Diarmaid Hughes


  1. Search for Dan I. Andersson in:

  2. Search for Diarmaid Hughes in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dan I. Andersson.



The capability of a genotype or individual to survive and reproduce.

Bypass resistance

The replacement (bypass) of a metabolic step that is normally inhibited by an antibiotic with a new, drug-resistant metabolic enzyme.

Pharmacokinetic properties

Characteristics of a drug that include: its mechanisms of absorption and distribution; the rate at which its action begins and the duration of the effect; the chemical changes of the agent in the body; and the effects and routes of excretion of drug metabolites. Often summarized as what the body does to a drug.

Pharmacodynamic properties

Characteristics of a drug that include: the physiological effects of a drug on the body, on microorganisms or on parasites in or on the body; the mechanisms of drug action; and the relationship between drug concentration and effect. Often summarized as what a drug does to the body.

Selection coefficient

A measure of the fitness of a phenotype relative to wild type (often denoted s), having a value between 0 and 1. When s = 0, there is no fitness reduction, and when s = 1, the mutation is lethal.


An interaction between genes such that the effect of one gene is modified by one or several other genes.

Gene conversion

A recombination event in which one strand of DNA is changed or repaired using information from another strand.


Value for the frequency of resistance before the intervention.

About this article

Publication history



Further reading