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  • Review Article
  • Published:

Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections

Key Points

  • Small colony variants (SCVs) of bacteria were first described almost 100 years ago. The first description of the SCV phenotype was for Salmonella enterica serovar Typhi (S. typhi), but SCVs have now been reported for a wide range of bacterial genera and species, including Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa. Most data have been collected for Staphylococcus aureus SCVs, so S. aureus SCVs are the focus of this Review article.

  • As their name implies, the most conspicuous feature of SCVs is their colony size — SCVs form colonies that are almost one-tenth the size of colonies associated with wild-type bacteria. In addition, SCVs have fastidious growth requirements and therefore present a challenge to clinical microbiologists.

  • In bacteria, slow growth can be caused by a variety of metabolic alterations. However, two defects are consistently associated with S. aureus SCVs isolated from clinical specimens: a deficiency in electron transport, and a deficiency in thymidine biosynthesis. Electron-transport-defective SCVs have a defect in the biosynthesis of menadione or haemin. Several mutations can produce the electron-transport-defective SCV phenotype, including mutations in menD and hemB, but the genetic basis of the electron-transport deficiency in vivo remains undefined and is a key area for future research. Curiously, the phenotype of thymidine-auxotrophic SCVs is nearly identical to that of SCVs with an electron-transport deficiency, and the basis for this is not understood. Again, the genetic basis of the thymidine deficiency in vivo is undefined and is a key area for future research. In this article, however, we propose that thymidine auxotrophs are double mutants, with a mutation in the gene that encodes NupC (a membrane-spanning protein involved in thymidine uptake) in addition to a mutation in the gene that encodes thymidylate synthase (ThyA).

  • The specific disease states associated with SCV infection that are discussed here include cystic fibrosis and osteomyelitis. For the past decade, researchers have been investigating the connection between the SCV phenotype and persistent, recurrent infections; however, in this Review, we highlight that S. aureus SCVs can also cause aggressive infections in humans and animal models, and we suggest that SCVs are part of the normal life cycle of staphylococci.

  • The incidence of SCVs in clinical specimens varies between studies and can be as high as 30% and as low as <1%. We suggest, however, that the SCV phenotype is not rare but, instead, is extremely difficult to recover. The issues that are associated with isolating and identifying SCVs in the clinical microbiology laboratory are also discussed.

Abstract

Small colony variants constitute a slow-growing subpopulation of bacteria with distinctive phenotypic and pathogenic traits. Phenotypically, small colony variants have a slow growth rate, atypical colony morphology and unusual biochemical characteristics, making them a challenge for clinical microbiologists to identify. Clinically, small colony variants are better able to persist in mammalian cells and are less susceptible to antibiotics than their wild-type counterparts, and can cause latent or recurrent infections on emergence from the protective environment of the host cell. This Review covers the phenotypic, genetic and clinical picture associated with small colony variants, with an emphasis on staphylococci, for which the greatest amount of information is available.

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Figure 1: Small colony variants.
Figure 2: Hypothetical model of the metabolic and energetic pathways that are associated with the small colony variant (SCV) phenotype.
Figure 3: Haemin-auxotrophic small colony variants.
Figure 4: Thymidine-auxotrophic small colony variants (SCVs).
Figure 5: Altered cellular morphology of haemin-auxotrophic small colony variants.

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References

  1. Proctor, R. A., Bates, D. M. & McNamara, P. J. in Emerging Infections Vol. 5 (ed. Craig, W.) 95–110 (American Society for Microbiology Press, Washington DC, 2001).

    Google Scholar 

  2. Jacobsen, K. A. Mitteilungen über einen variablen Typhusstamm (Bacterium typhi mutabile), sowie über eine eigentümliche hemmende Wirkung des gewöhnlichen agar, verursacht durch autoklavierung. Zentralbl. Bakteriol. [Orig. A] 56, 208–216 (1910) (in German).

    Google Scholar 

  3. Jensen, J. Biosynthesis of hematin compounds in a hemin requiring strain of Micrococcus pyogenes var. aureus. I. The significance of coenzyme A for the terminal synthesis of catalase. J. Bacteriol. 73, 324–333 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Bulger, R. J. A methicillin-resistant strain of Staphylococcus aureus. Clinical and laboratory experience. Ann. Intern. Med. 67, 81–89 (1967).

    CAS  PubMed  Google Scholar 

  5. Baddour, L. M., Barker, L. P., Christensen, G. D., Parisi, J. T. & Simpson, W. A. Phenotypic variation of Staphylococcus epidermidis in infection of transvenous endocardial pacemaker electrodes. J. Clin. Microbiol. 28, 676–679 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. von Eiff, C. et al. Bloodstream infections caused by small-colony variants of coagulase-negative staphylococci following pacemaker implantation. Clin. Infect. Dis. 29, 932–934 (1999).

    CAS  PubMed  Google Scholar 

  7. Bryan, L. E. & Kwan, S. Aminoglycoside-resistant mutants of Pseudomonas aeruginosa deficient in cytochrome d, nitrate reductase, and aerobic transport. Antimicrob. Agents Chemother. 19, 958–964 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Häussler, S. et al. Fatal outcome of lung transplantation in cystic fibrosis patients due to small-colony variants of the Burkholderia cepacia complex. Eur. J. Clin. Microbiol. Infect. Dis. 22, 249–253 (2003).

    PubMed  Google Scholar 

  9. Duff, D. C. B. Dissociation in Bacillus salmonicida with special reference to the appearance of G form of cultures. J. Bacteriol. 34, 49–58 (1937).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Swingle, E. L. Studies on small colony variants of Staphylococcus aureus. Proc. Soc. Exp. Biol. Med. 31, 891–893 (1934).

    Google Scholar 

  11. Hadley, P., Delves, E. & Klimek, J. The filterable forms of bacteria. I. A filterable stage in the life history of the Shiga dysentery bacillus. J. Infect. Dis. 48, 1–16 (1931).

    Google Scholar 

  12. Hall, W. H. & Spink, W. W. In vitro sensitivity of Brucella to streptomycin — development of resistance during streptomycin treatment. Proc. Soc. Exp. Biol. Med. 64, 403–406 (1947).

    CAS  PubMed  Google Scholar 

  13. Colwell, C. A. Small colony variants of Escherichia coli. J. Bacteriol. 52, 417–422 (1946).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kopeloff, N. Dissociation and filtration of Lactobacillus acidophilus. J. Infect. Dis. 55, 368–389 (1934).

    Google Scholar 

  15. Muhammad, M., Miller, F. E., Schor, J. & Kocka, F. E. Small-colony forms of enteric bacteria after exposure to aminoglycosides. Am. J. Clin. Pathol. 72, 79–81 (1979).

    Google Scholar 

  16. Raven, C. Dissociation of the gonococcus. J. Infect. Dis. 55, 328–334 (1934).

    Google Scholar 

  17. Seifert, H., von Eiff, C. & Fätkenheuer, G. Fatal case due to methicillin-resistant Staphylococcus aureus small colony variants in an AIDS patient. Emerg. Infect. Dis. 5, 450–453 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kipp, F. et al. Detection of Staphylococcus aureus by 16S rRNA directed in situ hybridisation in a patient with a brain abscess caused by small colony variants. J. Neurol. Neurosurg. Psychiatry 74, 1000–1002 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sherris, J. C. Two small colony variants of Staphylococcus aureus isolated in pure culture from closed infected lesions and their carbon dioxide requirements. J. Clin. Pathol. 5, 354–355 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Thomas, M. E. M. & Cowlard, J. H. Studies on a CO2-dependent Staphylococcus. J. Clin. Pathol. 8, 288–291 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Goudie, J. G. & Goudie, R. B. Recurrent infection by a stable-dwarf-colony variant of Staphylococcus aureus. J. Clin. Pathol. 8, 284–287 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Slifkin, M., Merkow, L. P., Kreuzberger, S. A., Engwall, C. & Pardo, M. Characterization of CO2 dependent microcolony variants of Staphylococcus aureus. Am. J. Clin. Pathol. 56, 584–592 (1971).

    CAS  PubMed  Google Scholar 

  23. Acar, J. F., Goldstein, F. W. & Lagrange, P. Human infections caused by thiamine- or menadione-requiring Staphylococcus aureus. J. Clin. Microbiol. 8, 142–147 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Lacy, R. W. Dwarf-colony variants of Staphylococcus aureus resistant to aminoglycoside antibiotics and to a fatty acid. J. Med. Microbiol. 2, 187–197 (1969).

    Google Scholar 

  25. Hale, J. H. Studies on Staphylococcus mutation: a naturally occurring 'G' gonidial variant and its carbon dioxide requirements. Br. J. Exp. Pathol. 32, 307–313 (1951).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wise, R. I. & Spink, W. W. The influence of antibiotics on the origin of small colonies (G variants) of Micrococcus pyogenes var. aureus. J. Clin. Invest. 33, 1611–1622 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wise, R. I. Small colonies (G variants) of staphylococci: isolation from cultures and infections. Ann. NY Acad. Sci. 65, 169–174 (1956).

    CAS  PubMed  Google Scholar 

  28. Spagna, V. A., Fass, R. J., Prior, R. B. & Slama, T. G. Report of a case of bacterial sepsis caused by a naturally occurring variant form of Staphylococcus aureus. J. Infect. Dis. 138, 277–278 (1978).

    CAS  PubMed  Google Scholar 

  29. Sompolinsky, D., Schwartz, D., Samra, Z., Steinmetz, J. & Siegman-Igra, Y. Septicemia with two distinct strains of Staphylococcus aureus and dwarf variants of both. Isr. J. Med. Sci. 21, 434–440 (1985).

    CAS  PubMed  Google Scholar 

  30. Baddour, L. M. & Christensen, G. D. Prosthetic valve endocarditis due to small-colony staphylococcal variants. Rev. Infect. Dis. 9, 1168–1174 (1987).

    CAS  PubMed  Google Scholar 

  31. Youmans, G. P. Production of small colony variants of Staphylococcus aureus. Proc. Soc. Exp. Biol. Med. 36, 94–96 (1937).

    Google Scholar 

  32. Nydahl, B. C. & Hall, W. L. The treatment of staphylococcal infection with nafcillin with a discussion of staphylococcal nephritis. Ann. Intern. Med. 63, 27–43 (1965).

    CAS  PubMed  Google Scholar 

  33. von Eiff, C. et al. Recovery of small colony variants of Staphylococcus aureus following gentamicin bead placement for osteomyelitis. Clin. Infect. Dis. 25, 1250–1251 (1997).

    CAS  PubMed  Google Scholar 

  34. Rolauffs, B., Bernhardt, T. M., von Eiff, C., Hart, M. L. & Bettin, D. Osteopetrosis, femoral fracture, and chronic osteomyelitis caused by Staphylococcus aureus small colony variants (SCV) treated by girdlestone resection — 6-year follow-up. Arch. Orthop. Trauma Surg. 122, 547–550 (2002). This paper describes a long-term prospective study identifying the role of SCVs.

    CAS  PubMed  Google Scholar 

  35. Borderon, E. & Horodniceanu, T. Mutants déficients a colonies naines de Staphylococcus: ètude de trois souches isolées chez des malades porteurs d'osteosyntheses. Ann. Microbiol. (Paris) 127, 503–514 (1976) (in French).

    CAS  Google Scholar 

  36. Hoffstadt, R. E. & Youmans, G. P. Staphylococcus aureus: dissociation and its relation to infection and to immunity. J. Infect. Dis. 51, 216–242 (1932).

    Google Scholar 

  37. von Eiff, C., Lindner, N., Proctor, R. A., Winkelmann, W. & Peters, G. Development of gentamicin-resistant small colony variants of Staphylococcus aureus after implantation of gentamicin beads in osteomyelitis as a possible cause of recurrence. Z. Orthop. Ihre Grenzgeb. 136, 268–271 (1998) (in German).

    CAS  PubMed  Google Scholar 

  38. Roggenkamp, A. et al. Chronic prosthetic hip infection caused by a small-colony variant of Escherichia coli. J. Clin. Microbiol. 36, 2530–2534 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kahl, B. et al. Persistent infection with small colony variant strains of Staphylococcus aureus in patients with cystic fibrosis. J. Infect. Dis. 177, 1023–1029 (1998).

    CAS  PubMed  Google Scholar 

  40. Sadowska, B. et al. Characteristics of Staphylococcus aureus, isolated from airways of cystic fibrosis patients, and their small colony variants. FEMS Immunol. Med. Microbiol. 32, 191–197 (2002).

    CAS  PubMed  Google Scholar 

  41. Kahl, B. C. et al. Population dynamics of persistent Staphylococcus aureus isolated from the airways of cystic fibrosis patients during a 6-year prospective study. J. Clin. Microbiol. 41, 4424–4427 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. von Eiff, C. et al. Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier's disease. Clin. Infect. Dis. 32, 1643–1647 (2001).

    CAS  PubMed  Google Scholar 

  43. Seifert, H., Wisplinghoff, H., Schnabel, P. & von Eiff, C. Small colony variants of Staphylococcus aureus and pacemaker-related infection. Emerg. Infect. Dis. 9, 1316–1318 (2003).

    PubMed  PubMed Central  Google Scholar 

  44. Lacy, R. W. & Mitchell, A. A. B. Gentamicin-resistant Staphylococcus aureus. Lancet 2, 1425–1426 (1969).

    Google Scholar 

  45. Sompolinsky, D., Cohen, M. & Ziv, G. Epidemiological studies on thiamine-less dwarf-colony variants of Staphylococcus aureus as etiologic agents of bovine mastitis. Infect. Immun. 9, 217–228 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Thomas, M. E. M. & Cowlard, J. H. Studies on a CO2-dependent Staphylococcus. J. Clin. Pathol. 8, 288–291 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Proctor, R. A., van Langevelde, P., Kristjansson, M., Maslow, J. N. & Arbeit, R. D. Persistent and relapsing infections associated with small colony variants of Staphylococcus aureus. Clin. Infect. Dis. 20, 95–102 (1995). This was the first paper to describe a distinct SCV-associated clinical syndrome.

    CAS  PubMed  Google Scholar 

  48. Proctor, R. A. in Gram-Positive Pathogens Ch. 35 (eds Fischetti, V. A., Novick, R. P., Ferretti, J. J., Portnoy, D. A. & Rood, J. I.) (American Society for Microbiology Press, Washington DC, in the press).

  49. Proctor, R. A. in Infections Associated with Indwelling Medical Devices Ch. 3 (eds Waldvogel, F. & Bisno, A. L.) 41–54 (American Society for Microbiology Press, Washington DC, 2000).

    Google Scholar 

  50. Proctor, R. A., Balwit, J. M. & Vesga, O. Variant subpopulations of Staphylococcus aureus as cause of persistent and recurrent infections. Infect. Agents Dis. 3, 302–312 (1994).

    CAS  PubMed  Google Scholar 

  51. Saxild, H. H., Andersen, L. N. & Hammer, K. dra-nupC-pdp operon of Bacillus subtilis: nucleotide sequence, induction by deoxyribonucleosides, and transcriptional regulation by the deoR-encoded DeoR repressor protein. J. Bacteriol. 178, 424–434 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Smith, K. M. et al. The broadly selective human Na+/nucleoside cotransporter (hCNT3) exhibits novel cation-coupled nucleoside transport characteristics. J. Biol. Chem. 280, 25436–25449 (2005).

    CAS  PubMed  Google Scholar 

  53. Slifkin, M., Merkow, L. P., Kreuzberger, S. A., Engwall, C. & Pardo, M. Characterization of CO2 dependent microcolony variants of Staphylococcus aureus. Am. J. Clin. Pathol. 56, 584–592 (1971).

    CAS  PubMed  Google Scholar 

  54. Ross, R. A. & Onderdonk, A. B. Production of toxic shock syndrome toxin 1 by Staphylococcus aureus requires both oxygen and carbon dioxide. Infect. Immun. 68, 5205–5209 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. von Eiff, C. et al. A site directed Staphylococcus aureus hemB mutant is a small colony variant which persists intracellularly. J. Bacteriol. 179, 4706–4712 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Bates, D. M. et al. Staphylococcus aureus menD and hemB mutants are as infective as the parent strains, but the menadione biosynthetic mutant persists within the kidney. J. Infect. Dis. 187, 1654–1661 (2003). This was the first animal model showing that genetically defined SCVs can persist in host tissues.

    PubMed  Google Scholar 

  57. Clements, M. O., Watson, S. P., Poole, R. K. & Foster, S. J. CtaA of Staphylococcus aureus is required for starvation survival, recovery, and cytochrome biosynthesis. J. Bacteriol. 181, 501–507 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cano, D. A., Pucciarelli, M. G., Martinez-Moya, M., Casadesus, J. & Garcia-del Portillo, F. Selection of small-colony variants of Salmonella enterica serovar Typhimurium in nonphagocytic eucaryotic cells. Infect. Immun. 71, 3690–3698 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Balwit, J. M., van Langevelde, P., Vann, J. M. & Proctor, R. A. Gentamicin-resistant menadione and hemin auxotrophic Staphylococcus aureus persist within cultured endothelial cells. J. Infect. Dis. 170, 1033–1037 (1994). This paper laid the biochemical basis for SCVs, identified interruption in electron transport as a link between many SCV phenotypes that had been previously reported, and showed that SCVs could persist in cultured mammalian cells.

    CAS  PubMed  Google Scholar 

  60. Vann, J. M. & Proctor, R. A. Cytotoxic effects of ingested Staphylococcus aureus on bovine endothelial cells: role of S. aureus α-hemolysin. Microb. Pathog. 4, 443–453 (1988). This paper showed that S. aureus can persist in mammalian cells and laid the groundwork for studies of SCVs.

    CAS  PubMed  Google Scholar 

  61. Vaudaux, P. et al. Increased expression of clumping factor and fibronectin-binding proteins by hemB mutants of Staphylococcus aureus expressing small colony variant phenotypes. Infect. Immun. 70, 5428–5437 (2002). This paper showed that SCVs have higher expression of surface adhesins than their isogenic parent and therefore have increased virulence despite their slow growth rate.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Baumert, N. et al. Physiology and antibiotic susceptibility of Staphylococcus aureus small colony variants. Microb. Drug Resist. 8, 253–260 (2002).

    CAS  PubMed  Google Scholar 

  63. Miller, M. H., Edberg, S. C., Mandel, L. J., Behar, F. C. & Steigbigel, N. H. Gentamicin uptake in wild type and aminoglycoside-resistant small colony mutants of Staphylococcus aureus. Antimicrob. Agents Chemother. 18, 722–729 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kohler, C. et al. Physiological characterization of a heme-deficient mutant of Staphylococcus aureus by a proteomic approach. J. Bacteriol. 185, 6928–6937 (2003). This paper describes the first detailed study of the changes occurring in metabolic pathways in SCVs.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Koo, S.-P., Bayer, A. S., Sahl, H.-G., Proctor, R. A. & Yeaman, M. R. Staphylocidal action of thrombin-induced platelet microbicidal protein (tPMP) is not solely dependent on transmembrane potential. Infect. Immun. 64, 1070–1074 (1996). This paper shows one mechanism by which SCVs could be more resistant to antibiotics.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Proctor, R. A. Bacterial energetics and antimicrobial resistance. Drug Resist. Updat. 1, 227–235 (1998).

    CAS  PubMed  Google Scholar 

  67. von Eiff, C., Friedrich, A. W., Becker, K. & Peters, G. Comparative in vitro activity of ceftobiprole against staphylococci displaying normal and small-colony variant phenotypes. Antimicrob. Agents Chemother. 49, 4372–4374 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Morton, H. E. & Shoemaker, J. The identification of Neisseria gonorrhoeae by means of bacterial variation and the detection of small colony forms in clinical material. J. Bacteriol. 50, 585–590 (1945).

    PubMed  PubMed Central  Google Scholar 

  69. Sasarman, A., Sanderson, K. E., Surdeanu, M. & Sonea, S. Hemin-deficient mutants of Salmonella typhimurium. J. Bacteriol. 102, 531–536 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bayer, A. S., Norman, D. C. & Kim, K. S. Characterization of Pseudomonas aeruginosa isolated during unsuccessful therapy of experimental endocarditis. Antimicrob. Agents Chemother. 31, 70–75 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Chinn, B. D. Characteristics of small colony variants with special reference to Shigella paradysenteriae sonne. J. Infect. Dis. 59, 137–151 (1936).

    Google Scholar 

  72. Chinn, B. D. Characteristics of small colony variants of Shigella paradysenteriae sonne and Staphylococcus aureus. Proc. Soc. Exp. Biol. Med. 34, 237–238 (1936).

    Google Scholar 

  73. Li, K., Farmer, J. J. & Coppola, A. A novel type of resistant bacteria induced by gentamicin. Trans. NY Acad. Sci. 36, 396–415 (1974).

    CAS  Google Scholar 

  74. Gilligan, P. H., Gage, P. A., Welch, D. F., Muszynski, M. J. & Wait, K. R. Prevalence of thymidine-dependent Staphylococcus aureus in patients with cystic fibrosis. J. Clin. Microbiol. 25, 1258–1261 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Stryer, L. in Biochemistry 739–762 (Freeman and Company, New York, 1995).

    Google Scholar 

  76. Kahl, B. C. et al. A thymidine-dependent small colony variant (SCV) has a 3 bp deletion in the thymidylate synthase (thy) gene and is complemented by a functional thy. Abstract BO200. Annual Meeting of the German Society of Hygiene and Microbiology (Goettingen, Germany, 25–28 Sep 2005).

  77. Kahl, B. C. et al. Thymidine-dependent small-colony variants of Staphylococcus aureus exhibit gross morphological and ultrastructural changes consistent with impaired cell separation. J. Clin. Microbiol. 41, 410–413 (2003).

    PubMed  PubMed Central  Google Scholar 

  78. Abell, E. L., Rosato, A. E., Archer, G. L. & Forbes, B. A. Clinical and microbiologic characterization of small colony variants (SCVs) of Staphylococcus aureus. Abstract D-052. American Society for Microbiology 105th General Meeting (Atlanta, Georgia, USA, 5–9 June 2005).

  79. Kahl, B. C. et al. Thymidine-dependent Staphylococcus aureus small colony variants are associated with extensive changes in regulator and virulence gene expression profiles. Infect. Immun. 73, 4119–4126 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Spearman, P. et al. Sternoclavicular joint septic arthritis with small-colony variant Staphylococcus aureus. Diagn. Microbiol. Infect. Dis. 26, 13–15 (1996).

    CAS  PubMed  Google Scholar 

  81. Abele-Horn, M., Schupfner, B., Emmerling, P., Waldner, H. & Goring, H. Persistent wound infection after herniotomy associated with small-colony variants of Staphylococcus aureus. Infection 28, 53–54 (2000).

    CAS  PubMed  Google Scholar 

  82. Adler, H., Widmer, A. & Frei, R. Emergence of a teicoplanin-resistant small colony variant of Staphylococcus epidermidis during vancomycin therapy. Eur. J. Clin. Microbiol. Infect. Dis. 22, 746–748 (2003).

    CAS  Google Scholar 

  83. von Eiff, C., Lubritz, G., Heese, C., Peters, G. & Becker, K. Effect of trimethoprim-sulfamethoxazole prophylaxis in AIDS patients on the formation of the small colony variant phenotype of Staphylococcus aureus. Diagn. Microbiol. Infect. Dis. 48, 191–194 (2004).

    CAS  PubMed  Google Scholar 

  84. Salgado, D. R., Boza, F. A., Pinto, M. & Sampaio, J. Outbreak with small colony variants of methicillin-resistant Staphylococcus aureus in an ICU. Abstract K-1226. 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago, Illinois, USA, 16–19 Dec 2001).

  85. Spanu, T. et al. Recurrent ventriculoperitoneal shunt infection caused by small-colony variants of Staphylococcus aureus. Clin. Infect. Dis. 41, 48–52 (2005).

    Google Scholar 

  86. Häussler, S., Tummler, B., Weissbrodt, H., Rohde, M. & Steinmetz, I. Small-colony variants of Pseudomonas aeruginosa in cystic fibrosis. Clin. Infect. Dis. 29, 621–625 (1999).

    PubMed  Google Scholar 

  87. Häussler, S., Rohde, M. & Steinmetz, I. Highly resistant Burkholderia pseudomallei small colony variants isolated in vitro and in experimental melioidosis. Med. Microbiol. Immunol. (Berl.) 188, 91–97 (1999).

    Google Scholar 

  88. von Götz, F. et al. Expression analysis of a highly adherent and cytotoxic small colony variant of Pseudomonas aeruginosa isolated from a lung of a patient with cystic fibrosis. J. Bacteriol. 186, 3837–3847 (2004).

    PubMed  PubMed Central  Google Scholar 

  89. Häussler, S. et al. Highly adherent small-colony variants of Pseudomonas aeruginosa in cystic fibrosis lung infection. J. Med. Microbiol. 52, 295–301 (2003).

    PubMed  Google Scholar 

  90. Häussler, S., Tummler, B., Weissbrodt, H., Rohde, M. & Steinmetz, I. Small-colony variants of Pseudomonas aeruginosa in cystic fibrosis. Clin. Infect. Dis. 29, 621–625 (1999).

    PubMed  Google Scholar 

  91. Fleiszig, S. M., Arora, S. K., Van, R. & Ramphal, R. FlhA, a component of the flagellum assembly apparatus of Pseudomonas aeruginosa, plays a role in internalization by corneal epithelial cells. Infect. Immun. 69, 4931–4937 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Badenoch, P. R. & Coster, D. J. Selection of gentamicin-resistant variants of Pseudomonas aeruginosa in the rat cornea. J. Ocul. Pharmacol. 5, 19–25 (1989).

    CAS  PubMed  Google Scholar 

  93. Chambers, H. F. & Miller, M. M. Emergence of resistance to cephalothin and gentamicin during combination therapy for methicillin-resistant Staphylococcus aureus endocarditis in rabbits. J. Infect. Dis. 155, 581–585 (1987).

    CAS  PubMed  Google Scholar 

  94. Musher, D. M., Baughn, R. E., Templeton, G. B. & Minuth, J. N. Emergence of variant forms of Staphylococcus aureus after exposure to gentamicin and infectivity of the variants in experimental animals. J. Infect. Dis. 136, 360–369 (1977).

    CAS  PubMed  Google Scholar 

  95. Wilson, S. G. & Sanders, C. C. Selection and characterization of strains of Staphylococcus aureus displaying unusual resistance to aminoglycosides. Antimicrob. Agents Chemother. 10, 519–525 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Chuard, C., Vaudaux, P. E., Proctor, R. A. & Lew, D. P. Decreased susceptibility to antibiotic killing of a stable small colony variant of Staphylococcus aureus in fluid phase and on fibronectin-coated surfaces. J. Antimicrob. Chemother. 39, 603–608 (1997). This paper showed that SCVs are extremely resistant to antibiotics when present as a biofilm and in stationary phase.

    CAS  PubMed  Google Scholar 

  97. Sinha, B. et al. Fibronectin-binding protein acts as Staphylococcus aureus invasion via fibronectin bridging to integrin α5β1 . Cell. Microbiol. 1, 101–117 (1999).

    CAS  PubMed  Google Scholar 

  98. Hudson, M. C., Ramp, W. K., Nicholson, N. C., Williams, A. S. & Nousiainen, M. T. Internalization of Staphylococcus aureus by cultured osteoblasts. Microb. Pathog. 19, 409–419 (1995).

    CAS  PubMed  Google Scholar 

  99. Hamill, R. J., Vann, J. M. & Proctor, R. A. Phagocytosis of Staphylococcus aureus by cultured bovine aortic endothelial cells: model for postadherence events in endovascular infections. Infect. Immun. 54, 833–836 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bayles, K. W. et al. Intracellular Staphylococcus aureus escapes the endosome and induces apoptosis in epithelial cells. Infect. Immun. 66, 336–342 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Kahl, B. C. et al. Staphylococcus aureus RN6390 replicates and induces apoptosis in a pulmonary epithelial cell line. Infect. Immun. 68, 5385–5392 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Dziewanowska, K. et al. Fibronectin binding protein and host cell tyrosine kinase are required for internalization of Staphylococcus aureus by epithelial cells. Infect. Immun. 67, 4673–4678 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Peacock, S. J., Foster, T. J., Cameron, B. J. & Berendt, A. R. Bacterial fibronectin-binding proteins and endothelial cell surface fibronectin mediate adherence of Staphylococcus aureus to resting human endothelial cells. Microbiology 145, 3477–3486 (1999).

    CAS  PubMed  Google Scholar 

  104. Vesga, O., Groeschel, M. C., Otten, M. F., Proctor, R. A. & Vann, J. M. Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. J. Infect. Dis. 173, 739–742 (1996). This paper showed that the host intracellular milieu (probably cationic peptides, as indicated in reference 65) can select for SCVs at an extremely high rate.

    CAS  PubMed  Google Scholar 

  105. Bantel, H. et al. α-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic pathway independently of death receptor signaling. J. Cell Biol. 155, 637–648 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Haslinger, B., Strangfeld, K., Peters, G., Schulze-Osthoff, K. & Sinha, B. Staphylococcus aureus α-toxin induces apoptosis in peripheral blood mononuclear cells: role of endogenous tumour necrosis factor-α and the mitochondrial death pathway. Cell. Microbiol. 5, 729–741 (2003).

    CAS  PubMed  Google Scholar 

  107. Quie, P. G. Microcolonies (G-variants) of Staphylococcus aureus. Yale J. Biol. Med. 41, 394–403 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Pelletier, L. L. Jr, Richardson, M. & Feist, M. Virulent gentamicin-induced small colony variants of Staphylococcus aureus. J. Lab. Clin. Med. 94, 324–334 (1979).

    PubMed  Google Scholar 

  109. Miller, M. H., Wexler, M. A. & Steigbigel, N. H. Single and combination antibiotic therapy of Staphylococcus aureus experimental endocarditis: emergence of gentamicin mutants. Antimicrob. Agents Chemother. 14, 336–343 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Brouillette, E., Martinez, A., Boyll, B. J., Allen, N. E. & Malouin, F. Persistence of a Staphylococcus aureus small-colony variant under antibiotic pressure in vivo. FEMS Immunol. Med. Microbiol. 41, 35–41 (2004).

    CAS  PubMed  Google Scholar 

  111. Jonsson, I.-M. et al. Virulence of a hemB mutant Staphylococcus aureus small colony variant in a murine model of septic arthritis. Microb. Pathog. 34, 73–79 (2003).

    CAS  PubMed  Google Scholar 

  112. Massey, R. C., Buckling, A. & Peacock, S. J. Phenotypic switching of antibiotic resistance circumvents permanent costs in Staphylococcus aureus. Curr. Biol. 11, 1810–1814 (2001). This report showed that SCVs form at a high rate.

    CAS  PubMed  Google Scholar 

  113. Massey, R. C. & Peacock, S. J. Antibiotic-resistant sub-populations of the pathogenic bacterium Staphylococcus aureus confer population-wide resistance. Curr. Biol. 12, R686–R687 (2002).

    CAS  PubMed  Google Scholar 

  114. Heinemann, M., Kummel, A., Ruinatscha, R. & Panke, S. In silico genome-scale reconstruction and validation of the Staphylococcus aureus metabolic network. Biotechnol. Bioeng. 92, 850–864 (2005).

    CAS  PubMed  Google Scholar 

  115. Proctor, R. A. & Peters, G. Small colony variants in staphylococcal infections: diagnostic and therapeutic implications. Clin. Infect. Dis. 27, 419–422 (1998).

    CAS  PubMed  Google Scholar 

  116. von Eiff, C. & Becker, K. in MRSA: Current Perspectives (eds Fluit, A. C. & Schmitz, F.-J.) 253–273 (Caister Academic, Wymondham, 2003).

    Google Scholar 

  117. Kipp, F. et al. Evaluation of two chromogenic agar media for recovery and identification of Staphylococcus aureus small colony variants. J. Clin. Microbiol. 43, 1956–1959 (2005).

    PubMed  PubMed Central  Google Scholar 

  118. Becker, K. et al. Development and evaluation of a quality-controlled ribosomal sequence database for 16S ribosomal DNA-based identification of Staphylococcus species. J. Clin. Microbiol. 42, 4988–4995 (2004). References 117 and 118 identify optimal conditions for the recovery of SCVs.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kipp, F., Becker, K., Peters, G. & von Eiff, C. Evaluation of different methods to detect methicillin resistance in small-colony variants of Staphylococcus aureus. J. Clin. Microbiol. 42, 1277–1279 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Borderon, E. & Horodniceanu, T. Metabolically deficient dwarf-colony mutants of Escherichia coli: deficiency and resistance to antibiotics of strains isolated from urine culture. J. Clin. Microbiol. 8, 629–634 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Borderon, E., Horodniceanu, T., Buissiere, J. & Barthez, J. P. Mutants déficients à colonies naines de Escherichia coli: ètude d'une souche thiamine-déficiente isolée d'une uroculture. Ann. Microbiol. (Paris) 128A, 413–417 (1977) (in French).

    CAS  Google Scholar 

  122. Morris, J. F., Barnes, C. G. & Sellers, T. F. An outbreak of typhoid fever due to the small colony variety of Eberthella typhosa. Am. J. Public Health 33, 246–248 (1943).

    CAS  Google Scholar 

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Acknowledgements

A list of additional references related to SCVs is available online (see Supplementary information S2 (box)). This work was supported by grants from the National Institutes of Health (United States) to R.A.P. and P.M., by a grant from the Bundesministerium für Bildung und Forschung (Germany) (Pathogenomic Network: Alliance Gram-positive cocci, Project staphylococci) to C.v.E., K.B. and G.P., and by grants from the Deutsche Forschungsgemeinschaft (Germany) to B.C.K. and C.v.E.

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DATABASES

Entrez Genome Project

Bacillus subtilis

Brucella melitensis

Enterobacter cloacae

Escherichia coli

Klebsiella pneumoniae

Lactobacillus acidophilus

Neisseria gonorrhoeae

Pseudomonas aeruginosa

Salmonella enterica

Serratia marcescens

Staphylococcus aureus

Staphylococcus epidermidis

Vibrio cholerae

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Proctor, R., von Eiff, C., Kahl, B. et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4, 295–305 (2006). https://doi.org/10.1038/nrmicro1384

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