Skip to main content

Advertisement

SpringerLink
Log in

Small colony variants of Staphylococcus aureus — review

  • Review
  • Published:
Folia Microbiologica Aims and scope Submit manuscript

Abstract

Bacterial variants of Staphylococcus aureus called small colony variants (SCVs) originate by mutations in metabolic genes, resulting in emergence of auxotrophic bacterial subpopulations. These variants are not particularly virulent but are able to persist viable inside host cells. SCVs show their characteristic auxotrophic growth deficiency and depressed α-cytotoxin activity. Environmental pressure such as antibiotics, select for isogenic SCV cells that are frequently found coexisting with their parent wild-type strains in a mixed bacterial culture. SCV strains often grow on blood agar as non-pigmented or pinpoint pigmented colonies and their key biochemical tests are often non-reactive. Their altered metabolism or auxotrophism can result in long generation time and thus SCV phenotype, more often than not SCV can be overgrown by their wild-type counterparts and other competitive respiratory flora. This could affect laboratory detection. Thus, molecular methods, such as 16S rRNA partial sequencing or amplification of species-specific DNA targets (e.g. coagulase, nuclease) directly from clinical material or isolated bacterial colonies, become the method of choice. Patients at risk of infection by S. aureus SCVs include cystic fibrosis patients (CF), patients with skin and foreign-body related infections and osteomyelitis, as they suffer from chronic staphylococcal infections and are subject to long-term antibiotic therapy. Molecular evidence of SCV development has not been found except for some random mutations of the thymidylate synthase gene (thyA) described in SCV S. aureus strains of CF patients. These variants are able to bypass the antibiotic effect of folic acid antagonists such as sulfonamides and trimethoprim. Resistance to gentamicin and aminoglycosides in the hemin or menadione auxotrophic SCVs was hypothesized as being due to decreased influx of the drugs into cells as a result of decreased ATP production and decreased electrochemical gradient on cell membranes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

CF:

cystic fibrosis (a genetic disorder)

CFTR:

(gene) gene for cystic fibrosis transmembrane conductase regulator

MLST:

multiple-locus sequence typing

MRSA:

methicillin-resistant S. aureus

PFGE:

pulsed field gel electrophoresis

SCVs:

small colony variants

spa (typing):

single-locus analysis of structural gene (spa) for protein A of S. aureus

thyA :

thymidylate synthase A gene

VNTR:

multiple-locus variable tandem repeat analysis

References

  • Abu-qatouseh L.F., Chinni S.V., Seggewiss J., Proctor R.A., Brosius J., Rozhdestvensky T.S., Peters G., VON Eiff C., Becker K.: Identification of differentially expressed small non-protein-coding RNAs in Staphylococcus aureus displaying both the normal and the small-colony variant phenotype. J.Mol.Med.88, 565–575 (2010)

    Article  CAS  PubMed  Google Scholar 

  • Anderson S.W., Stapp J.R., Burns J.L., Qin X.: Characterization of small-colony-variant Stenotrophomonas maltophilia isolated from the sputum specimens of five patients with cystic fibrosis. J.Clin.Microbiol.45, 529–535 (2007).

    Article  CAS  PubMed  Google Scholar 

  • 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).

    CAS  PubMed  Google Scholar 

  • Becker K., Friedrich A.W., Lubritz G., Weilert M., Peters G., VON Eiff C.: Prevalence of genes encoding pyrogenic toxin superantigens and exfoliative toxins among strains of Staphylococcus aureus isolated from blood and nasal specimens. J.Clin. Microbiol.41, 1434–1439 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Becker K., Harmsen D., Mellmann A., Meier C., Schumann P., Peters G., VON Eiff C.: Development and evaluation of a qualitycontrolled ribosomal sequence database for 16S ribosomal DNA-based identification of Staphylococcus species. J.Clin. Microbiol.42, 4988–4995 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Becker K., Laham N.A., Fegeler W., Proctor R.A., Peters G., VON Eiff C.: Fourier-transform infrared spectroscopic analysis is a powerful tool for studying the dynamic changes in Staphylococcus aureus small-colony variants. J.Clin.Microbiol.44, 3274–3278 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Bentley R., Meganathan R.: Biosynthesis of vitamin K (menaquinone) in bacteria. Microbiol.Rev.46, 241–280 (1982).

    CAS  PubMed  Google Scholar 

  • Besier B., Smaczny C., Mallinckrodt C., Krahl A., Ackerman H., Brade V., Wichelhaus T.A.: Prevalence and clinical significance of Staphylococcus aureus small-colony variants in cystic fibrosis lung disease. J.Clin.Microbiol.45, 168–172 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Besier S., Zander J., Siegel E., Saum S.H., Hunfeld K.P., Ehrhart A., Brade V., Wichelhaus T.A.: Thymidine-dependent Staphylococcus aureus small-colony variants: human pathogens that are relevant not only in cases of cystic fibrosis lung disease. J.Clin.Microbiol.46, 3829–3832 (2008).

    Article  PubMed  Google Scholar 

  • 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  Google Scholar 

  • Browning C.H., Adamson H.S.: Stable dwarf-colony forms produced Staphylococcus pyogenes. J.Pathol.Bacteriol.62, 499–500 (1950).

    Google Scholar 

  • 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 

  • Chatterjee I., Herrmann M., Proctor R.A., Peters G., Kahl B.C.: Enhanced post-stationary-phase-survival of a clinical thymidine-dependent small-colony variant of Staphylococcus aureus results from lack of a functional tricarboxylic acid cycle. J.Bacteriol.189, 2936–2940 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Chatterjee I., Kriegeskorte A., Fischer A., Deiwick S., Theimann N., Proctor R.A., Peters G., Herrmann M., Kahl B.C.: In vivo mutations of thymidylate synthase (encoded by thyA) are responsible for thymidine dependency in clinical small-colony variants of Staphylococcus aureus. J.Bacteriol.190, 834–842 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Devriese L.A.: Hemin-dependent mutants isolated from methicillin-resistant Staphylococcus aureus strains. Antoine van Leeuwenhoek39, 33–40 (1973).

    Article  CAS  Google Scholar 

  • von Eiff C.: Staphylococcus aureus small colony variants: a challenge to microbiologist and clinicians. Internat.J.Antimicrob.Agents31, 507–510 (2008).

    Article  Google Scholar 

  • von Eiff C., Becker K.: Small-colony variants (SCVs) of staphylococci: a role in foreign body-associated infections. Internat. J.Artur.Organs30, 778–785 (2007).

    Google Scholar 

  • von Eiff C., Bettin D., Proctor R.A., Rolauffs B., Lindner N., Winkelmann W., Peters G.: Recovery of small colony variants of Staphylococcus aureus following gentamicin bead placement for osteomyelitis. Clin.Infect.Dis.25, 1250–1251 (1997a).

    Article  Google Scholar 

  • von Eiff C., Heilmann C., Proctor R.A., Woltz C., Peters G., Gotz F.: A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persist intracellulary. J.Bacteriol.179, 4706–4712 (1997b).

    Google Scholar 

  • von Eiff C., Vaudaux P., Kahl B.C., Lew D., Emler S., Schmidt A., Peters G., Proctor R.A.: Bloodstream infections caused by small colony variants of coagulase negative staphylococci following pacemaker implantation. Clin.Infect.Dis.29, 932–934 (1999).

    Article  Google Scholar 

  • von Eiff C., Becker K., Metze D., Lubritz G., Hockmann J., Scwartz T., Peters G.: 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).

    Article  Google Scholar 

  • von Eiff C., Mcnamara P., Becker K., Bates D., Lei X.H., Ziman M., Bochner B.R., Peters G., Proctor R.A.: Phenotype microarray profilig of Staphylococcus aureus menD and hemB mutants with small-colony-variant phenotype. J.Bacteriol.188, 687–693 (2006).

    Article  Google Scholar 

  • Enright M.C., Day N.P.J., Davies C.E., Peacock S.J., Spratt B.G.: Multilocus sequence typing for characterization of methicillin-resistant and methicillin-susceptible clones of Staphylococcus aureus. J.Clin.Microbiol.38, 1008–1015 (2000).

    CAS  PubMed  Google Scholar 

  • Fischer A., VON Eiff C., Kuczius T., Omoe K., Peters G., Becker K.: A quantitative real-time immuno-PCR approach for detection of staphylococcal enterotoxins. J.Mol.Med.85, 461–469 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Garzoni C., Kelley W.L.: Staphylococcus aureus: new evidence for intracellular persistence. Trends Microbiol.17, 59–65 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Häussler S., Ziegler I., Löttel A., VON Götz F., Rohde M., Wehmhöhner D., Saravanamuthu S., Tümmler B., Steinmetz I.: Highly adherent small-colony variants of Pseudomonas aeruginosa in cystic fibrosis lung infection. J.Med.Microbiol.22, 295–301 (2003).

    Article  Google Scholar 

  • Høiby N., Krogh Johansen H., Moser C., Song Z., Ciofu O., Kharazmi A.: Pseudomonas aeruginosa and the in vitro and in vivo biofilm mode of growth. Microbes Infect.3, 23–35 (2001).

    Article  PubMed  Google Scholar 

  • Johnson W.M., Tyler S.D., Ewan E.P., Ashton F.E., Pollard D.R., Rozee K.R.: Detection of genes for enterotoxins, exfoliative toxins, and toxic shock syndrome toxin 1 in Staphylococcus aureus by the polymerase chain reaction. J.Clin.Microbiol.29, 426–430 (1991).

    CAS  PubMed  Google Scholar 

  • Kahl B., Herrmann M., Everding A.S., Koch H.G., Becker K., Harms E., Proctor R.A., Peters G.: Persistent infection with small colony variant strains of Staphylococcus aureus in patient with cystic fibrosis. J.Infect.Dis.177, 1023–1029 (1998).

    CAS  PubMed  Google Scholar 

  • Kahl B., Duebbers A., Lubritz G., Haeberle J., Koch H.G., Ritzerfeld B., Reilly M., Harms E., Proctor R.A., Herrmann M., Peters G.: 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 (2003a).

    Article  CAS  PubMed  Google Scholar 

  • Kahl B., Belling G., Reichelt R., Herrmann M., Proctor R.A., Peters G.: 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 (2003b).

    Article  PubMed  Google Scholar 

  • Kaplan M.L., Dye W.: Growth requirements of some small-colony-forming variants of Staphylococcus aureus. J.Clin.Microbiol.4, 343–348 (1976).

    CAS  PubMed  Google Scholar 

  • 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).

    Article  CAS  PubMed  Google Scholar 

  • Kipp F., Kahl B., Becker K., Baron E.J., Proctor R.A., Peters G., VON Eiff C.: Evaluation of two chromogenic agar media for recovery and identification of Staphylococcus aureus small-colony variants. J.Clin.Microbiol.43, 1956–1959 (2005).

    Article  PubMed  Google Scholar 

  • Koh K.S., Lam K.W., Alhede M., Queck S.Y., Labbate M., Kjelleberg S., Rice S.A.: Phenotypic diversification and adaptation of Serratia marcescens MG1 biofilm-derived morphotypes. J.Bacteriol.189, 119–130 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Kohler C., VON Eiff C., Peters G., Proctor R.A., Hecker M., Engelmann S.: Physiological characterization of a heme-deficient mutant of Staphylococcus aureus by a proteomic approach. J.Bacteriol.185, 6928–6937 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Lacey R.W.: Dwarf-colony variants of Staphylococcus aureus resistant to aminoglycoside antibiotics and to fatty acids. J.Med.Microbiol.2, 187–197 (1969).

    Article  CAS  PubMed  Google Scholar 

  • Lacey R.W., Mitchell A.B.: Gentamicin-resistant Staphylococcus aureus. Lancet2, 1425–1426 (1969).

    Article  CAS  PubMed  Google Scholar 

  • Lånnergård J., VON Eiff C., Sander G., Cordes T., Seggewiss J., Peters G., Proctor R.A., Becker K., Hughes D.: Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of S. aureus. Antimicrob.Agents Chemother.52, 4017–4022 (2008).

    Article  PubMed  Google Scholar 

  • Lina G., Piémont Y., Godail-Gamot F., Bes M., Peter M.O., Gauduchon V., Vandenesch F., Etienne J.: Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin.Infect.Dis.29, 1128–1132 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Lyczak J.B., Cannon C.L., Pier G.B.: Lung infections associated with cystic fibrosis. Clin.Microbiol.Rev.15, 194–222 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Malone J.G., Jaeger T., Spangler C., Ritz D., Spang A., Arrieumerlou C., Kaever V., Landmann R., Jenal U.: YfiBNR mediates cyclic di-GMP dependent small colony variant formation and persistence in Pseudomonas aeruginosa. PLoS Pathogens12, e1000804 (2010).

    Article  Google Scholar 

  • 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).

    Article  CAS  PubMed  Google Scholar 

  • Menzies B.E., Kernodle D.S.: Site-directed mutagenesis of the α-toxin gene of Staphylococcus aureus: role of histidines in toxin activity in vitro and in a murine model. Infect.Immun.62, 1843–1847 (1994).

    CAS  PubMed  Google Scholar 

  • 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, 585–587 (1945).

    Google Scholar 

  • National Food Institute, Technical University of Denmark: Multiplex PCR for the detection of the mecA gene; http://www.eurlar.eu/data/images/meca-pcr_protocol%2006.02.08.pdf (2008).

  • Oliver A., Cantón R., Campo P., Baquero F., Blázquez J.: High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science288, 1251–1254 (2000).

    Article  CAS  PubMed  Google Scholar 

  • 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).

    CAS  PubMed  Google Scholar 

  • Proctor R.A., Kah B., VON Eiff C., Vaudaux P.E., Lew D.P., Peters G.: Staphylococcal small colony variants have novel mechanisms for antibiotic resistance. Clin.Inf.Dis.27, S68–S74 (1998).

    Article  Google Scholar 

  • Proctor R.A., VON Eiff C., Kahl B.C., Becker K., Mcnamara P., Herrmann M., Peters G.: Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat.Rev.Microbiol.4, 295–305 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Sabat A., Malachova N., Miedzobrodzki J., Hryniewicz W.: Comparison of PCR-based methods for typing Staphylococcus aureus isolates. J.Clin.Microbiol.44, 3804–3807 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Sadowska B., Bonar A., VON Eiff C., Proctor R.A., Chmiela M., Rudnicka W., Róźalska B.: Characteristics of Staphylococcus aureus, isolated from airways of cystic fibrosis patients, and their small colony variants. FEMS Immunol.Med.Microbiol.32, 191–197 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Schaaff F., Bierbaum G., Baumert N., Bartmann P., Sahl H.G.: Mutations are involved in emergence of aminoglycoside-induced small colony variants of Staphylococcus aureus. Internat.J.Med.Microbiol.293, 427–435 (2003).

    Article  CAS  Google Scholar 

  • Schneider M., Mühlemann K., Droz S., Couzinet S., Casaulta C., Zimmerli S.: Clinical characteristics associated with isolation of small-colony variants of Staphylococcus aureus and Pseudomonas aeruginosa from respiratory secretions of patients with cystic fibrosis. J.Clin.Microbiol.46, 1832–1834 (2008).

    Article  PubMed  Google Scholar 

  • Schnitzer R.J., Canagni L.J., Back M.: Resistence of small colony variants (G forms) of a Staphylococcus toward the bacteriostatic activity of penicillin. Proc.Soc.Exp.Biol.Med.53, 75–78 (1943).

    CAS  Google Scholar 

  • Seggewiss J., Becker K., Kotte O., Eisenacher M., Yazdi M.R., Fischer A., Mcnamara P., AL Laham N., Proctor R.A., Peters G., Heinemann M., VON Eiff C.: Reporter metabolite analysis of a trancriptional profiles of a Staphylococcus aureus strain with normal phenotype and its isogenic hemB mutant displaying the small-colony-variant phenotype. J.Bacteriol.188, 7765–7777 (2006).

    Article  CAS  PubMed  Google Scholar 

  • 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).

    Article  CAS  PubMed  Google Scholar 

  • Seifert H., Oltmanns D., Becker K., Wisplinghoff H, VON Eiff C.: Staphylococcus lugdunensis pacemaker-related infection. Emerg.Infect.Dis.11, 1283–1286 (2005).

    PubMed  Google Scholar 

  • Sendi P., Proctor R.A.: Staphylococcus aureus as an intracellular pathogen: the role of small colony variants. Trends Microbiol.17, 54–58 (2009).

    Article  CAS  PubMed  Google Scholar 

  • 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).

    Article  CAS  PubMed  Google Scholar 

  • Sinha B., Fraunholz M.: Staphylococcus aureus host cell invasion and post-invasion events. Internat.J.Med.Microbiol.300, 170–175 (2010).

    Article  Google Scholar 

  • Sinha B., Herrmann M.: Mechanism and consequences of invasion of endothelial cells by S. aureus. Tromb.Haemost.94, 266–277 (2005).

    CAS  Google Scholar 

  • Stokes J.L., Bayne H.G.: Dwarf colony mutant of Salmonellae. J.Bacteriol.76, 136–141 (1958).

    CAS  PubMed  Google Scholar 

  • Tebbutt T.M., Coleman D.J.: Evaluation of some methods for the laboratory examination of sputum. J.Clin.Pathol.31, 724–729 (1978).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Tuchscherr L., Heitmann V., Hussain M., Viemann D., Roth J., VON Eiff C., Peters G., Becker K., Löffler B.: Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. J.Infect.Dis.202, 1031–1040 (2010).

    Article  PubMed  Google Scholar 

  • Vesga O., Groeschel M.C., Otten M.F., Brar D.W., Vann J.M., Proctor R.A.: Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. J.Infect.Dis.173, 739–742 (1996).

    CAS  PubMed  Google Scholar 

  • Wise R.I., Spink W.W.: The influence of antibiotics on the origin of small colonies (G variants) of Micrococcus pyogenes var. aureus. 45th Annual Meet. American Society for Clinical Investigation (1953).

  • Youmans G.P., Delves E.: The effect of inorganic salts on the production of small colony variants by Staphylococcus aureus. J.Bacteriol.44, 127–136 (1942).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Microbiology, 2nd Medical Faculty, Charles University in Prague, Prague 5-Motol, Czech Republic

    O. Melter & B. Radojevič

Authors
  1. O. Melter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Radojevič
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. Melter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Melter, O., Radojevič, B. Small colony variants of Staphylococcus aureus — review . Folia Microbiol 55, 548–558 (2010). https://doi.org/10.1007/s12223-010-0089-3

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12223-010-0089-3

Keywords

Search

Navigation