Review

Microbiological effects of sublethal levels of antibiotics

  • Nature Reviews Microbiology volume 12, pages 465478 (2014)
  • doi:10.1038/nrmicro3270
  • Download Citation
Published:

Abstract

The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

  • Subscribe to Nature Reviews Microbiology for full access:

    $265

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , & Evolution of antimicrobial resistance among Enterobacteriaceae (focus on extended spectrum β-lactamases and carbapenemases). Expert Opin. Pharmacother. 14, 199–210 (2013).

  2. 2.

    & Antibiotic-resistant bacteria: a challenge for the food industry. Crit. Rev. Food Sci. Nutr. 53, 11–48 (2013).

  3. 3.

    et al. Ready for a world without antibiotics? The Pensieres Antibiotic Resistance Call to Action. Antimicrob. Resist. Infect. Control 1, 11 (2012).

  4. 4.

    Multidrug-resistant Tuberculosis. Med. Clin. North Amer. 97, 553–579 (2013).

  5. 5.

    et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin. Microbiol. Infect. 18, E37–E45 (2012).

  6. 6.

    Antibiotic dosing in critical illness. J. Antimicrob. Chemother. 66, (suppl. 2), i25–i31 (2011).

  7. 7.

    & Mechanisms of antibiotic resistance in bacteria. Annu. Rev. Biochem. 42, 471–506 (1973).

  8. 8.

    , , & Mechanisms of action of and resistance to ciprofloxacin. Am. J. Med. 82, 12–20 (1987).

  9. 9.

    et al. Prevalence of antibiotic resistance genes and their relationship with antibiotics in the Huangpu River and the drinking water sources, Shanghai, China. Sci. Total Environ. 458, 267–272 (2013).

  10. 10.

    & Occurrence and concentrations of pharmaceutical compounds in groundwater used for public drinking-water supply in California. Sci. Total Environ. 409, 3409–3417 (2011).

  11. 11.

    , , , & Occurrence and abundance of antibiotics and resistance genes in rivers, canal and near drug formulation facilities — a study in Pakistan. PloS ONE 8, e62712 (2013).

  12. 12.

    , & Antibiotics and antibiotic resistance in water environments. Curr. Opin. Biotechnol. 19, 260–265 (2008).

  13. 13.

    The complex dynamics of antimicrobial activity in the human gastrointestinal tract. Trans. Am. Clin. Climatol. Associ. 124, 123–132 (2013).

  14. 14.

    , , & Antibiotic-selective environments. Clin. Infect. Dis. 27 (Suppl. 1), 5–11 (1998). This study is among the first to explore the potential importance of low levels of antibiotics for the selection and evolution of resistance, and the potential clinical importance of low-level resistant mutants.

  15. 15.

    & Selective compartments for resistant microorganisms in antibiotic gradients. Bioessays 19, 731–736 (1997).

  16. 16.

    Some effects of subinhibitory concentrations of antibiotics on bacteria. Bull. NY Acad. Med. 51, 1046–1055 (1975).

  17. 17.

    et al. Antibiotic resistance is ancient. Nature 477, 457–461 (2011). This study applies metagenomic analysis to ancient samples to demonstrate the existence of a diverse collection of genes that confer resistance to clinically used antibiotics, long before antibiotics were used in medicine.

  18. 18.

    , & Detecting risk and predicting patient mortality in patients with extended-spectrum β-lactamase-producing Enterobacteriaceae bloodstream infections. Future Microbiol. 7, 1173–1189 (2012).

  19. 19.

    , , , & Prescribing for children — taste and palatability affect adherence to antibiotics: a review. Arch. Dis. Childhood 97, 293–297 (2012).

  20. 20.

    , , & Pharmacokinetic–pharmacodynamic considerations in the design of hospital-acquired or ventilator-associated bacterial pneumonia studies: look before you leap! Clin. Infecti. Diseases 51, S103–S110 (2010).

  21. 21.

    & Systematic review of factors contributing to penicillin treatment failure in Streptococcus pyogenes pharyngitis. Otolaryngol.-Head Neck Surg. 137, 851–857 (2007).

  22. 22.

    , , , & Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori. Ann. Intern. Med. 139, 483–487 (2003).

  23. 23.

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

  24. 24.

    , , , & Prolonged impact of a one-week course of clindamycin on Enterococcus spp. in human normal microbiota. Scand. J. Infect. Dis. 41, 215–219 (2009).

  25. 25.

    et al. Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage. J. Antimicrob. Chemother. 52, 645–650 (2003).

  26. 26.

    , , , & Dose imprecision and resistance: free-choice medicated feeds in industrial food animal production in the United States. Environ. Health Persp. 119, 279–283 (2011).

  27. 27.

    & Does adding routine antibiotics to animal feed pose a serious risk to human health? BMJ 347, f4214 (2013).

  28. 28.

    Get pigs off antibiotics. Nature 486, 465–466 (2012).

  29. 29.

    (ed.) Antimicrobial Agents: Antibacterials and Antifungals (ASM Press, 2005).

  30. 30.

    Antibiotics in the aquatic environment — a review — part I. Chemosphere 75, 417–434 (2009).

  31. 31.

    Environmental pollution by antibiotics and by antibiotic resistance determinants. Environ. Poll. 157, 2893–2902 (2009).

  32. 32.

    & Fluoroquinolone antibiotics in the environment. Rev. Environ. Contamin. Toxicol. 191, 131–162 (2007).

  33. 33.

    & Evolution of antibiotic resistance at non-lethal drug concentrations. Drug Resist. Updat. 15, 162–172 (2012).

  34. 34.

    Pharmaceutical antibiotic compounds in soils — a review. J. Plant Nutr. Soil Sci. 166, 145–167 (2003).

  35. 35.

    , & Aquatic systems: maintaining, mixing and mobilising antimicrobial resistance? Trends Ecol. Evol. 26, 278–284 (2011).

  36. 36.

    & Fluoroquinolones in soil — risks and challenges. Anal. Bioanal. Chem. 387, 1287–1299 (2007).

  37. 37.

    Antimicrobial use in food and companion animals. Anim. Health Res. Rev. 9, 127–133 (2008).

  38. 38.

    et al. Residues of fluoroquinolones in marine aquaculture environment of the Pearl River Delta, South China. Environ. Geochem. Health 34, 323–335 (2012).

  39. 39.

    , , & Occurrence of antimicrobial residues in pasteurized milk commercialized in the state of Parana, Brazil. J. Food Prot. 72, 911–914 (2009).

  40. 40.

    et al. Antibiotic residues in food: the African scenario. Jpn J. Vet. Res. 61, S13–S22 (2013).

  41. 41.

    , , , & Emerging food contaminants: a review. Anal. Bioanal. Chem. 398, 2413–2427 (2010).

  42. 42.

    , & Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J. Hazard. Mater. 148, 751–755 (2007). This study shows that effluent from a waste-water plant serving several drug manufacturers contained extremely high concentrations of several broad-spectrum antibiotics.

  43. 43.

    et al. Contamination of surface, ground, and drinking water from pharmaceutical production. Environ. Toxicol. Chem. 28, 2522–2527 (2009).

  44. 44.

    & Mutant selection window hypothesis updated. Clin. Infect. Dis. 44, 681–688 (2007).

  45. 45.

    & Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin. Infect. Dis. 33 S147–S156 (2001).

  46. 46.

    et al. Selection of resistant bacteria at very low antibiotic concentrations. PLoS Pathog. 7, e1002158 (2011). This study uses competition experiments to accurately measure the MSCs of antibiotics that are selective for resistant mutants.

  47. 47.

    et al. Selective advantage of resistant strains at trace levels of antibiotics: a simple and ultrasensitive color test for detection of antibiotics and genotoxic agents. Antimicrob. Agents Chemother. 55, 1204–1210 (2011). This study describes a method to detect the presence of selective concentrations of antibiotics (or other growth inhibitors) in liquid culture, using bacterial strains tagged with distinguishable chromogenic markers.

  48. 48.

    et al. Clonal expansion during Staphylococcus aureus infection dynamics reveals the effect of antibiotic intervention. PLoS Pathog. 10, e1003959 (2014).

  49. 49.

    et al. Occurrence of antibiotics as emerging contaminant substances in aquatic environment. Int. J. Environ. Health Res. 23, 296–310 (2013).

  50. 50.

    , & in EcoSal — Escherichia coli and Salmonella: Cellular and Molecular Biology ch. 5.6.6 (eds Böck, A., et al.) (ASM Press, 2011).

  51. 51.

    General mechanisms of antimicrobial resistance. Rev. Infect. Dis. 1, 23–29 (1979).

  52. 52.

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

  53. 53.

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

  54. 54.

    & Selection of resistance at lethal and non-lethal antibiotic concentrations. Curr. Opin. Microbiol. 15, 555–560 (2012).

  55. 55.

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

  56. 56.

    & Antibiotic resistance and its cost: is it possible to reverse resistance? Nature Rev. Microbiol. 8, 260–271 (2010).

  57. 57.

    , , & Proliferation of mutators in a cell population. J. Bacteriol. 179, 417–422 (1997). This important study shows that exposure of a bacterial population to different successive selective pressures results in a very high probability of the selection of mutators.

  58. 58.

    , & Streptomycin, suppression, and the code. Proc. Natl Acad. Sci. USA 51, 883–890 (1964).

  59. 59.

    & Altered enzymes in ageing human fibroblasts. Nature 238, 26–30 (1972).

  60. 60.

    The error catastrophe: a molecular Fata Morgana. Bioessays 6, 33–35 (1987).

  61. 61.

    , , & Does streptomycin cause an error catastrophe? Biochimie 69, 131–136 (1987).

  62. 62.

    Translational errors as the cause of mutations in Escherichia coli. Mol. Gen. Genet. 231, 469–471 (1992).

  63. 63.

    , , , & Antibiotic stress induces genetic transformability in the human pathogen Streptococcus pneumoniae. Science 313, 89–92 (2006).

  64. 64.

    et al. Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci. Mol. Microbiol. 56, 836–844 (2005).

  65. 65.

    , & SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 427, 72–74 (2004). This study finds that induction of the SOS response in V. cholerae by exposure to ciprofloxacin relieves repression of an ICE that encodes multiple antibiotic resistance genes and induces its conjugative transfer.

  66. 66.

    , , & Antibiotic-mediated recombination: ciprofloxacin stimulates SOS-independent recombination of divergent sequences in Escherichia coli. Mol. Microbiol. 64, 83–93 (2007). This paper shows that the fluoroquinolone ciprofloxacin increases genetic variation by stimulating homologous recombination between divergent sequences.

  67. 67.

    & Effect of subinhibitory concentrations of antibiotics on intrachromosomal homologous recombination in Escherichia coli. Antimicrob. Agents Chemother. 53, 3411–3415 (2009).

  68. 68.

    et al. Evidence for induction of integron-based antibiotic resistance by the SOS response in a clinical setting. PLoS Pathog. 8, e1002778 (2012).

  69. 69.

    , , & Development of resistance and cross-resistance in Pseudomonas aeruginosa exposed to subinhibitory antibiotic concentrations. APMIS 107, 585–592 (1999).

  70. 70.

    , & Effect of subinhibitory concentrations of antibiotics on mutation frequency in Streptococcus pneumoniae. J. Antimicrob. Chemother. 57, 849–854 (2006).

  71. 71.

    & Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance. Antimicrob. Agents Chemother. 55, 2438–2441 (2011). This study shows that several different classes of antibiotics at subinhibitory levels induce the SOS response in V. cholerae, resulting in increased rates of genetic change.

  72. 72.

    , & Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol. Cell 37, 311–320 (2010).

  73. 73.

    , & RpoS plays a central role in the SOS induction by sublethal aminoglycoside concentrations in Vibrio cholerae. PLoS Genet. 9, e1003421 (2013).

  74. 74.

    et al. Effect of recA inactivation on mutagenesis of Escherichia coli exposed to sublethal concentrations of antimicrobials. J. Antimicrob. Chemother. 66, 531–538 (2011).

  75. 75.

    , , , & Influence of ciprofloxacin and vancomycin on mutation rate and transposition of IS256 in Staphylococcus aureus. Int. J. Med. Microbiol. 301, 229–236 (2011).

  76. 76.

    et al. β-lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity. Nature Commun. 4, 1610 (2013).

  77. 77.

    et al. Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J. Infect. Dis. 181, 664–670 (2000).

  78. 78.

    et al. Molecular analysis of antibiotic resistance gene clusters in Vibrio cholerae O139 and O1 SXT constins. Antimicrob. Agents Chemother. 45, 2991–3000 (2001).

  79. 79.

    & Circulation and transmission of clones of Vibrio cholerae during cholera outbreaks. Curr. Top. Microbiol. Immunol. (2014).

  80. 80.

    , , & Gene cassettes and cassette arrays in mobile resistance integrons. FEMS Microbiol. Rev. 33, 757–784 (2009).

  81. 81.

    , & Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220 (2011).

  82. 82.

    et al. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 343, 204–208 (2014).

  83. 83.

    , & SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet. 5, e1000760 (2009). This important paper shows that ciprofloxacin can result in the formation of E. coli persisters via a mechanism that depends on induction of the SOS response.

  84. 84.

    & Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PLoS Genet. 9, e1003123 (2013).

  85. 85.

    & Introducing the parvome: bioactive compounds in the microbial world. ACS Chem. Biol. 7, 252–259 (2012).

  86. 86.

    Small molecules: the missing link in the central dogma. Nature Chem. Biol. 1, 64–66 (2005).

  87. 87.

    Specialized microbial metabolites: functions and origins. J. Antibiot. 66, 361–364 (2013).

  88. 88.

    , & Antibiotics as signalling molecules. Phil. Trans. R. Soc. Lond. B Biol. Sci. 362, 1195–1200 (2007).

  89. 89.

    , & The truth about antibiotics. Int. J. Med. Microbiol. 296, 163–170 (2006).

  90. 90.

    , , & Antibiotics as selectors and accelerators of diversity in the mechanisms of resistance: from the resistome to genetic plasticity in the β-lactamases world. Front. Microbiol. 4, 9 (2013).

  91. 91.

    , & Phenazines and other redox-active antibiotics promote microbial mineral reduction. Appl. Environ. Microbiol. 70, 921–928 (2004).

  92. 92.

    , & Endogenous phenazine antibiotics promote anaerobic survival of Pseudomonas aeruginosa via extracellular electron transfer. J. Bacteriol. 192, 365–369 (2010).

  93. 93.

    The role of antibiotics and antibiotic resistance in nature. Environ. Microbiol. 11, 2970–2988 (2009).

  94. 94.

    & Antibiotics as signals that trigger specific bacterial responses. Curr. Opin. Microbiol. 11, 161–167 (2008).

  95. 95.

    , & The world of subinhibitory antibiotic concentrations. Curr. Opin. Microbiol. 9, 445–453 (2006).

  96. 96.

    , , & Redox-active antibiotics control gene expression and community behavior in divergent bacteria. Science 321, 1203–1206 (2008). This important paper re-evaluates the functional roles of 'antibiotic' secondary metabolites in Streptomyces coelicolor and P. aeruginosa and shows that they have conserved functions in gene regulation and population behaviour.

  97. 97.

    , , & Antibiotics as signal molecules. Chem. Rev. 111, 5492–5505 (2011).

  98. 98.

    et al. Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach. Antimicrob. Agents Chemother. 50, 1680–1688 (2006).

  99. 99.

    et al. A low concentration of azithromycin inhibits the mRNA expression of N-acyl homoserine lactone synthesis enzymes, upstream of lasI or rhlI, in Pseudomonas aeruginosa. Pulm. Pharmacol. Ther. 22, 483–486 (2009).

  100. 100.

    , & Bacterial interference caused by autoinducing peptide variants. Science 276, 2027–2030 (1997).

  101. 101.

    et al. Revisiting quorum sensing: discovery of additional chemical and biological functions for 3-oxo-N-acylhomoserine lactones. Proc. Natl Acad. Sci. USA 102, 309–314 (2005).

  102. 102.

    et al. Antibacterial activity of a competence-stimulating peptide in experimental sepsis caused by Streptococcus pneumoniae. Antimicrob. Agents Chemother. 48, 4725–4732 (2004).

  103. 103.

    , , , & Molecular basis of florfenicol-induced increase in adherence of Staphylococcus aureus strain Newman. J. Antimicrob. Chemother. 56, 315–323 (2005).

  104. 104.

    et al. Induction of fibronectin adhesins in quinolone-resistant Staphylococcus aureus by subinhibitory levels of ciprofloxacin or by sigma B transcription factor activity is mediated by two separate pathways. Antimicrob. Agents Chemother. 49, 916–924 (2005).

  105. 105.

    et al. Aminoglycoside antibiotics induce bacterial biofilm formation. Nature 436, 1171–1175 (2005). This study shows that subinhibitory concentrations of aminoglycosides induce biofilm formation as part of a defence response in E. coli and P. aeruginosa, which is mediated by alterations in the level of cyclic-di-GMP.

  106. 106.

    , & Subinhibitory clindamycin differentially inhibits transcription of exoprotein genes in Staphylococcus aureus. Infect. Immun. 69, 2996–3003 (2001).

  107. 107.

    et al. Effects of subinhibitory concentrations of antibiotics on virulence factor expression by community-acquired methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 68, 1524–1532 (2013).

  108. 108.

    et al. Effects of mupirocin at subinhibitory concentrations on flagella formation in Pseudomonas aeruginosa and Proteus mirabilis. J. Antimicrob. Chemother. 51, 1175–1179 (2003).

  109. 109.

    , & Subinhibitory concentrations of antibiotics affect stress and virulence gene expression in Listeria monocytogenes and cause enhanced stress sensitivity but do not affect Caco-2 cell invasion. J. Appl. Microbiol. 113, 1273–1286 (2012).

  110. 110.

    , , , & Effect of antibiotics on group A Streptococcus exoprotein production analyzed by two-dimensional gel electrophoresis. Antimicrob. Agents Chemother. 49, 88–96 (2005).

  111. 111.

    et al. Regulation of Salmonella typhimurium virulence gene expression by cationic antimicrobial peptides. Mol. Microbiol. 50, 219–230 (2003).

  112. 112.

    , , & Subinhibitory concentrations of β-lactam induce haemolytic activity in Staphylococcus aureus through the SaeRS two-component system. FEMS Microbiol. Lett. 268, 98–105 (2007).

  113. 113.

    , & Ciprofloxacin and trimethoprim cause phage induction and virulence modulation in Staphylococcus aureus. Antimicrob. Agents Chemother. 50, 171–177 (2006).

  114. 114.

    , , & Modulation of Salmonella gene expression by subinhibitory concentrations of quinolones. J. Antibiot. 64, 73–78 (2011).

  115. 115.

    & Side effects of antibiotics on genetic variability. FEMS Microbiol. Rev. 33, 531–538 (2009).

  116. 116.

    et al. Effect of abolishment of the use of antimicrobial agents for growth promotion on occurrence of antimicrobial resistance in fecal enterococci from food animals in Denmark. Antimicrob. Agents Chemother. 45, 2054–2059 (2001).

  117. 117.

    , , , & Usage of veterinary therapeutic antimicrobials in Denmark, Norway and Sweden following termination of antimicrobial growth promoter use. Prev. Vet. Med. 75, 123–132 (2006).

  118. 118.

    & Antimicrobial resistance in Scandinavia after ban of antimicrobial growth promoters. Anim. Biotechnol. 17, 147–156 (2006).

  119. 119.

    , & Restricting antimicrobial use in food animals: lessons from Europe. Microbe 6, 274–279 (2011).

  120. 120.

    , & Fluxes of 13 selected pharmaceuticals in the water cycle of Stockholm, Sweden. Water Sci. Technol. 63, 1772–1780 (2011).

  121. 121.

    , , & Ozonation and advanced oxidation technologies to remove endocrine disrupting chemicals (EDCs) and pharmaceuticals and personal care products (PPCPs) in water effluents. J. Hazard. Mater. 149, 631–642 (2007).

  122. 122.

    et al. Isolation and characterization of methicillin-resistant Staphylococcus aureus from pork farms and visiting veterinary students. PloS ONE 8, e53738 (2013).

  123. 123.

    et al. Livestock-associated methicillin and multidrug resistant Staphylococcus aureus is present among industrial, not antibiotic-free livestock operation workers in North Carolina. PloS ONE 8, e67641 (2013).

  124. 124.

    et al. Staphylococcus aureus CC398: host adaptation and emergence of methicillin resistance in livestock. mBio 3 (2012).

  125. 125.

    et al. Distinguishable epidemics of multidrug-resistant Salmonella Typhimurium DT104 in different hosts. Science 341, 1514–1517 (2013).

  126. 126.

    , , , & Compensatory gene amplification restores fitness after inter-species gene replacements. Mol. Microbiol. 75, 1078–1089 (2010).

  127. 127.

    , & Periodic selection in Escherichia coli. Proc. Natl Acad. Sci. USA 37, 146–155 (1951).

  128. 128.

    Pertinence of periodic selection phenomenon to prokaryote evolution. Genetics 77, 127–142 (1974).

  129. 129.

    & Lessons from 50 years of SOS DNA-damage-induced mutagenesis. Nature Rev. Mol. Cell Biol. 8, 587–594 (2007).

  130. 130.

    SOS repair hypothesis: phenomenology of an inducible DNA repair which is accompanied by mutagenesis. Basic life sci. 5A, 355–367 (1975).

  131. 131.

    , , & Evolutionary theory of bacterial quorum sensing: when is a signal not a signal? Phil. Trans. R. Soc. Lond. B, Biol. Sci. 362, 1241–1249 (2007).

  132. 132.

    , & Bacterial cell-to-cell communication: sorry, can't talk now — gone to lunch! Curr. Opin. Microbiol. 5, 216–222 (2002).

  133. 133.

    , , , & Microbial responses to microgravity and other low-shear environments. Microbiol. Mol. Biol. Rev. 68, 345–361 (2004).

  134. 134.

    , , & Bacterial charity work leads to population-wide resistance. Nature 467, 82–85 (2010).

  135. 135.

    et al. Transcriptional modulation of bacterial gene expression by subinhibitory concentrations of antibiotics. Proc. Natl Acad. Sci. USA 99, 17025–17030 (2002). This groundbreaking study shows that, at subinhibitory concentrations, the antibiotics erythromycin and rifampicin modulate transcription from hundreds of different promoters in S. Typhimurium.

  136. 136.

    , , & Transcription modulation of Salmonella enterica serovar Typhimurium promoters by sub-MIC levels of rifampin. J. Bacteriol. 188, 7988–7991 (2006).

  137. 137.

    , & Separate mechanisms are involved in rifampicin upmodulated and downmodulated gene expression in Salmonella Typhimurium. Res. Microbiol. 164, 416–424 (2013).

  138. 138.

    et al. Protein interactions in genome maintenance as novel antibacterial targets. PLoS ONE 8, e58765 (2013).

  139. 139.

    et al. Comparison of the changes in global gene expression of Escherichia coli induced by four bactericidal agents. J. Mol. Microbiol. Biotechnol. 5, 105–122 (2003).

  140. 140.

    , , & Global expression of prophage genes in Escherichia coli O157:H7 strain EDL933 in response to norfloxacin. Antimicrob. Agents Chemother. 49, 931–944 (2005).

  141. 141.

    , & Toxin gene expression by shiga toxin-producing Escherichia coli: the role of antibiotics and the bacterial SOS response. Emerg. Infect. Dis. 6, 458–465 (2000).

  142. 142.

    et al. PBP3 inhibition elicits adaptive responses in Pseudomonas aeruginosa. Mol. Microbiol. 62, 84–99 (2006).

  143. 143.

    & Determination of the genetic similarities of fingerprints from Escherichia coli O157:H7 isolated from different sources in the North West Province, South Africa using ISR, BOXAIR and REP-PCR analysis. Microbiol. Res. 168, 438–446 (2013).

  144. 144.

    , , , & Global transcriptional response of Bacillus subtilis to treatment with subinhibitory concentrations of antibiotics that inhibit protein synthesis. Antimicrob. Agents Chemother. 49, 1915–1926 (2005).

  145. 145.

    , , & Influence of clindamycin on the stability of coa and fnbB transcripts and adherence properties of Staphylococcus aureus Newman. FEMS Microbiol. Lett. 252, 73–78 (2005).

  146. 146.

    et al. Dual effects of MLS antibiotics: transcriptional modulation and interactions on the ribosome. Chem. Biol. 11, 1307–1316 (2004).

  147. 147.

    , , , & Transcriptional regulation and signature patterns revealed by microarray analyses of Streptococcus pneumoniae R6 challenged with sublethal concentrations of translation inhibitors. J. Bacteriol. 185, 359–370 (2003).

  148. 148.

    , , & Genome-wide transcriptional profiling of the Escherichia coli response to a proline-rich antimicrobial peptide. Antimicrob. Agents Chemother. 48, 3260–3267 (2004).

  149. 149.

    , , & Transcriptional profile of the Escherichia coli response to the antimicrobial insect peptide cecropin A. Antimicrob. Agents Chemother. 47, 1–6 (2003).

  150. 150.

    , , , & CesRK, a two-component signal transduction system in Listeria monocytogenes, responds to the presence of cell wall-acting antibiotics and affects β-lactam resistance. Antimicrob. Agents Chemother. 47, 3421–3429 (2003).

  151. 151.

    & Subinhibitory cerulenin inhibits staphylococcal exoprotein production by blocking transcription rather than by blocking secretion. Microbiology 151, 3059–3069 (2005).

  152. 152.

    , , & Pattern of induction of colicin E9 synthesis by sub MIC of Norfloxacin antibiotic. Microbiol. Res. 168, 661–666 (2013).

  153. 153.

    et al. Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus haemolyticus: methicillin-resistant isolates are detected directly in blood cultures by multiplex PCR. Microbiol. Res. 165, 243–249 (2010).

  154. 154.

    et al. SOS response induction by β-lactams and bacterial defense against antibiotic lethality. Science 305, 1629–1631 (2004). This interesting study shows that β-lactam antibiotics can induce the SOS response, which transiently halts cell division and enables cells to survive an otherwise lethal antibiotic exposure.

  155. 155.

    et al. In vitro interference of tigecycline at subinhibitory concentrations on biofilm development by Enterococcus faecalis. J. Antimicrob. Chemother. 67, 1155–1158 (2012).

  156. 156.

    & Tetracycline-dependent appearance of plasmidlike forms in Bacteroides uniformis 0061 mediated by conjugal Bacteroides tetracycline resistance elements. J. Bacteriol. 170, 1651–1657 (1988).

  157. 157.

    , & The region of a Bacteroides conjugal chromosomal tetracycline resistance element which is responsible for production of plasmidlike forms from unlinked chromosomal DNA might also be involved in transfer of the element. J. Bacteriol. 172, 4271–4279 (1990).

  158. 158.

    , , & Translational control of tetracycline resistance and conjugation in the Bacteroides conjugative transposon CTnDOT. J. Bacteriol. 187, 2673–2680 (2005).

  159. 159.

    & Circularization of Tn916 is required for expression of the transposon-encoded transfer functions: characterization of long tetracycline-inducible transcripts reading through the attachment site. Mol. Microbiol. 28, 103–117 (1998).

  160. 160.

    , , , & Inducible transfer of conjugative transposon Tn1545 from Enterococcus faecalis to Listeria monocytogenes in the digestive tracts of gnotobiotic mice. Antimicrob. Agents Chemother. 35, 185–187 (1991).

  161. 161.

    , , & β-lactam antibiotics increase the frequency of plasmid transfer in Staphylococcus aureus. J. Antimicrob. Chemother. 17, 409–413 (1986).

Download references

Acknowledgements

D.I.A. and D.H. are supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Governmental Agency for Innovation Systems, the Knut and Alice Wallenberg Foundation, the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) (to D.I.A), and the European Union Seventh framework program EvoTAR project (to D.I.A.).

Author information

Affiliations

  1. Department of Medical Biochemistry and Microbiology, BOX 582, Biomedical Center, Uppsala University, SE-75123 Uppsala, Sweden.

    • Dan I. Andersson
    •  & Diarmaid Hughes

Authors

  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.

Glossary

Minimal inhibitory concentration

(MIC). The lowest concentration of an antibiotic that, under a defined set of experimental conditions, inhibits visible growth of a bacterial culture.

Antibiotic gradients

The gradual increases or decreases in antibiotic concentration that are observed between two spatially segregated sites (for example, two tissues in the body).

Aquaculture

The farming of aquatic organisms such as fish, mollusks and aquatic plants.

Minimal selective concentration

(MSC). The lowest concentration of an antibiotic that results in the selection of a resistant mutant in a population over an isogenic susceptible strain.

Mutational space

All possible mutations that can confer a specific phenotype. This can vary from one to several mutations, depending on the system that is studied.

FACS

(Fluorescence-activated cell sorting). A laser-based technology that is used for cell sorting and cell counting, in which fluorescently tagged suspended cells pass through an electronic detection apparatus.

Periodic selection

A type of natural selection in which diversity within a bacterial population is recurrently purged owing to the emergence of adaptive mutants that outcompete other bacteria in the population.

Selection coefficient

A measure of the relative fitness of a strain or phenotype (it can also be used to refer to selective differences between genotypes).

Fitness cost

In the context of this review, the reduction in growth and reproductive potential that accompanies a resistance mutation or other genetic change.

Mutator bacteria

Bacteria with increased mutation rates; they are typically the result of inactivating mutations in DNA repair systems (such as the mismatch-repair system).

SOS response

A global response to DNA damage in which cell growth is arrested and DNA repair and mutagenesis are induced. The key proteins that are involved are RecA and LexA.

Integrative conjugative elements

(ICEs). Mobile genetic elements in bacterial chromosomes; they have the ability to be transferred between cells by conjugation. They encode the integrative ability of bacteriophages and transposons and the transfer mechanism of conjugative plasmids.

RecBCD pathway

A pathway of homologous recombination that utilizes the enzyme complex RecBCD and targets DNA with double-strand breaks. It requires RecA for strand invasion.

RecFOR pathway

A pathway of homologous recombination that involves the enzymes RecJ and RecFOR. It primarily functions on DNA with single-strand breaks and requires RecA for strand invasion.

Mismatch-repair system

A strand-specific DNA-repair system that is present in most organisms; it recognizes and repairs erroneous DNA replication and recombination and DNA damage.

Sigma factors

Transcription factors that target RNA polymerase to specific gene promoters during the initiation of transcription.

Secondary metabolites

Organic compounds that are not directly involved in the normal growth, development and reproduction of an organism.

Competence

A transient physiological state in which bacteria are proficient in the uptake of extracellular DNA. Natural competence is usually regulated in response to environmental signals.

Exoprotein

An extracellular protein. Examples include haemolysin, nuclease and protease, which are exported by Staphylococcus aureus and are involved in the lysis of eukaryotic host cells.

Biocides

Toxic chemicals (or sometimes organisms) that have an inhibitory effect on a living organism (such as a bacterium).