SpringerProtocols: Abstract: The Integron/Gene Cassette System: An Active Player in Bacterial Adaptation

6. The Integron/Gene Cassette System: An Active Player in Bacterial Adaptation

By: Maurizio Labbate⁵, Rebecca Josephine Case⁶, Hatch W. Stokes⁵

Abstract

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The integron includes a site-specific recombination system capable of integrating and expressing genes contained in structures called mobile gene cassettes. Integrons were originally identified on mobile elements from pathogenic bacteria and were found to be a major reservoir of antibiotic-resistance genes. Integrons are now known to be ancient structures that are phylogenetically diverse and, to date, have been found in approximately 9% of sequenced bacterial genomes. Overall, gene diversity in cassettes is extraordinarily high, suggesting that the integron/gene cassette system has a broad role in adaptation rather than being confined to simply conferring resistance to antibiotics. In this chapter, we provide a review of the integron/gene cassette system highlighting characteristics associated with this system, diversity of elements contained within it, and their importance in driving bacterial evolution and consequently adaptation. Ideas on the evolution of gene cassettes and gene cassette arrays are discussed.

Affiliation(s): (5) Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia
(6) Harvard Center for the Environment (HUCE) and Microbiology and Molecular Genetics, Harvard Medical School, Harvard University, Boston, MA, USA

Book Title: Horizontal Gene Transfer: Genomes in Flux

Series: Methods in Molecular Biology | Volume: 532 | Pub. Date: Jan-30-2009 | Page Range: 103-125 | DOI: 10.1007/978-1-60327-853-9_6

Subject: Genetics/Genomics

Key Words: Integron - gene cassette - antibiotic-resistance - attC

References

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1.	Collis, C., Hall, R. (1995) Expression of antibiotic resistance genes in the integrated cassettes of integrons. Antimicrob Agents Chemother 39, 155–162.

2.	Collis, C. M., Grammaticopoulos, G., Briton, J., Stokes, H. W., Hall, R. M. (1993) Site-specific insertion of gene cassettes into integrons. Mol Microbiol 9, 41–52.

3.	Recchia, G. D., Hall, R. M. (1995) Gene cassettes, a new class of mobile element. Microbiology 141, 3015–3027.

4.	Rowe-Magnus, D. A., Guerout, A.-M., Mazel, D. (1999) Super-integrons. Res Microbiol 150, 641–651.

5.	Leverstein-van Hall, M. A., Paauw, A., Box, A. T. A., Blok, H. E. M., Verhoef, J., Fluit, A. C. (2002) Presence of integron-associated resistance in the community is widespread and contributes to multidrug resistance in the hospital. J Clin Microbiol 40, 3038–3040.

6.	Leverstein-van Hall, M. A., Adrienne, T., A, Blok, H. E. M., Paauw, A., Fluit, A. C., Verhoef, J. (2002) Evidence of extensive interspecies transfer of integron-mediated antimicrobial resistance genes among multidrug-resistant Enterobacteriaceae in a clinical setting. J Infect Dis 186, 49–56.

7.	Maguire, A. J., Brown, D. F. J., Gray, J. J., Desselberger, U. (2001) Rapid screening technique for class 1 integrons in Enterobacteriaceae and nonfermenting gram-negative bacteria and its use in molecular epidemiology. Antimicrob Agents Chemother 45, 1022–1029.

8.	Martinez-Freijo, P., Fluit, A. C., Schmitz, F. J., Grek, V. S. C., Verhoef, J., Jones, M. E. (1998) Class 1 integrons in gram-negative isolates from different European hospitals and association with decreased susceptibility to multiple antibiotic compounds. J Antimicrob Chemother 42, 689–696.

9.	Sallen, B., Rajoharison, A., Desvarenne, S., Mabilat, C. (1995) Molecular epidemiology of integron-associated antibiotic resistance genes in clinical isolates of Enterobacteriaceae. Microb Drug Resist 1, 195–202.

10.	Tauch, A., Gotker, S., Puhler, A., Kalinowski, J., Thierbach, G. (2002) The 27.8-kb R-plasmid pTET3 from Corynebacterium glutamicum encodes the aminoglycoside adenyltransferase gene cassette aadA9 and the regulated tetracycline efflux system Tet 33 flanked by active copies of the widespread insertion sequence IS 6100. Plasmid 48, 117–129.

11.	Shi, L., Zheng, M., Xiao, Z., Asakura, M., Su, J., Li, L., Yamasaki, S. (2006) Unnoticed spread of class 1 integrons in gram-positive clinical strains isolated in Guangzhou, China. Microbiol Immunol 50, 463–467.

12.	Nesvera, J., Hochmannova, J., Patek, M. (1998) An integron of class 1 is present on the plasmid pCG4 from a gram-positive bacterium Corynebacterium glutamicum.FEMS Microbiol Lett 169, 391–395.

13.	Nandi, S., Maurer, J. J., Hofacre, C., Summers, A. O. (2004) Gram-positive bacteria are a major reservoir of class 1 antibiotic resistance integrons in poultry litter. Proc Natl Acad Sci U S A 101, 7118–7122.

14.	Xu, Z., Shi, L., Zhang, C., Zhang, L., Li, X., Cao, Y., Li, L., Yamasaki, S. (2007) Nosocomial infection caused by class 1 integron-carrying Staphylococcus aureus in a hospital in South China. Clin Microbiol Infect 13, 980–984.

15.	Boucher, Y., Labbate, M., Koenig, J. E., Stokes, H. (2007) Integrons: mobilizable platforms that promote genetic diversity in bacteria. Trends Microbiol 15, 301–309.

16.	Mazel, D. (2006) Integrons: agents of bacterial evolution. Nat Rev Microbiol 4, 608–620.

17.	Stokes, H. W., Holmes, A. J., Nield, B. S., Holley, M. P., Nevalainen, K. M. H., Mabbutt, B. C., Gillings, M. R. (2001) Gene cassette PCR: sequence-independent recovery of entire genes from environmental DNA. Appl Environ Microbiol 67, 5240–5246.

18.	Holmes, A. J., Gillings, M. R., Nield, B. S., Mabbutt, B. C., Nevalainen, K. M. H., Stokes, H. W. (2003) The gene cassette metagenome is a basic resource for bacterial genome evolution. Environ Microbiol 5, 383–394.

19.	Stokes, H. W., O’Gorman, D. B., Recchia, G. D., Parsekhian, M., Hall, R. M. (1997) Structure and function of 59-base element recombination sites associated with mobile gene cassettes. Mol Microbiol 26, 731–745.

20.	MacDonald, D., Demarre, G., Bouvier, M., Mazel, D., Gopaul, D. N. (2006) Structural basis for broad DNA-specificity in integron recombination. Nature 440, 1157–1162.

21.	Rowe-Magnus, D. A., Guerout, A.-M., Ploncard, P., Dychinco, B., Davies, J., Mazel, D. (2001) The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons. Proc Natl Acad Sci U S A 98, 652–657.

22.	Paulsen, I. T., Littlejohn, T. G., Rådstrom, P., Sundström, L., Sköld, O., Swedberg, G., Skurray, R. A. (1993) The 3′ conserved segment of integrons contains a gene associated with multidrug resistance to antiseptics and disinfectants. Antimicrob Agents Chemother 37, 761–768.

23.	Sundström, L., Rådstrom, P., Swedberg, G., (1988) Site-specific recombination promotes linkage between trimethoprim- and sulfonamide-resistance genes. Sequence characterization of dhfrV and sulI and a recombination active locus of Tn 21. Mol Gen Genet 213, 191–201.

24.	Kholodii, G. Y., Mindlin, S. Z., Bass, I. A., Yurieva, O. V., Minakhina, S. V., Nikiforov, V. G. (1995) Four genes, two ends, and a res region are involved in transposition of Tn5053: a paradigm for a novel family of transposons carrying either a mer operon or an integron. Mol Microbiol 17, 1189–1200.

25.	Brown, H. J., Stokes, H. W., Hall, R. M. (1996) The integrons In0, In2 and In5 are defective transposon derivatives. J Bacteriol 178, 4429–4437.

26.	Rådstrom, P., Sköld, O., Swedberg, G., Flensburg, J., Roy, P.H., Sundström, L. (1994) Transposon Tn5090 of plasmid R751, which carries an integron, is related to Tn7, Mu, and the retroelements. J Bacteriol 176, 3257–3268.

27.	Kamali-Moghaddam, M., Sundström, L. (2000) Transposon targeting determined by resolvase. FEMS Microbiol. Lett. 186, 55–59.

28.	Partridge, S. R., Recchia, G. D., Stokes, H. W., Hall, R. M. (2001) Family of class 1 integrons related to In4 from Tn1 696. Antimicrob Agents Chemother 45, 3014–3020.

29.	Stokes, H. W., Nesbø, C., L, Holley, M., Bahl, I. M., Gillings, M. R., Boucher, Y. (2006) Class 1 integrons potentially predating the association with Tn402-like transposition genes are present in a sediment microbial community. J Bacteriol 188, 5722–5730.

30.	Collis, C. M., Kim, M.-J., Partridge, S. R., Stokes, H. W., Hall, R. M. (2002) Characterization of the class 3 integron and the site-specific recombination system it determines. J Bacteriol 184, 3017–3026.

31.	Arakawa, Y., Murakami, M., Suzuki, K., Ito, H., Wacharotayankun, E., Ohsuka, S., Kato, N., Ohta, M. (1995) A novel integron-like element carrying the metallo-B-lactamase gene bla–IMP–. Antimicrob Agents Chemother 39, 1612–1615.

32.	Correia, M., Boavida, F., Grosso, F., Salgado, M. J., Lito, L. M., Cristino, J. M., Mendo, S., Duarte, A. (2003) Molecular characterization of a new class 3 integron in Klebsiella pneumoniae. Antimicrob Agents Chemother 47, 2838–2843.

33.	Xu, H., Davies, J., Miao, V. (2007) Molecular characterization of class 3 integrons from Delftia spp. J Bacteriol 189, 6276–6283.

34.	Hansson, K., Sundström, L., Pelletier, A., Roy, P. H. (2002) IntI2 integron integrase in Tn 7. J Bacteriol 184, 1712–1721.

35.	Biskri, L., Mazel, D. (2003) Erythromycin esterase gene ere(A) is located in a functional gene cassette in an unusual class 2 integron. Antimicrob Agents Chemother 47, 3326–3331.

36.	Ramirez, M. S., Quiroga, C., Centrón, D. (2005) Novel rearrangement of a class 2 integron in two non-epidemiologically related isolates of Acinetobacter baumanii. Antimicrob Agents Chemother 49, 5179–5181.

37.	Ramirez, M. S., Vargas, L. J., Cagnoni, V., Tokumoto, M., Centrón, D. (2005) Class 2 integron with a novel cassette array in a Burkholderia cenocepacia isolate. Antimicrob Agents Chemother 49, 4418–4420.

38.	Ahmed, A. M., Nakano, H., Shimamoto, T. (2005) Molecular characterization of integrons in non-typhoid Salmonella serovars isolated in Japan: description of an unusual class 2 integron. Antimicrob Agents Chemother 55, 371–374.

39.	Heikkilä, E., Sundström, L., Skurnik, M., Houvinen, P. (1991) Analysis of genetic localization of the type 1 trimethoprim resistance gene from Escherichia coli isolated in Finland. Antimicrob Agents Chemother 35, 1562–1569.

40.	Lichtenstein, C., Brenner, S. (1982) Unique insertion site of Tn7 in the E. coli chromosome. Nature 297, 601–603.

41.	Wolkow, C. A., DeBoy, R. T., Craig, N. L. (1996) Conjugative plasmids are preferred targets for Tn 7. Genes Dev 10, 2145–2157.

42.	Barlow, R. S., Gobius, K. S. (2006) Diverse class 2 integrons in bacteria from beef cattle sources. J Antimicrob Chemother 58, 1133–1138.

43.	Hochhut, B., Lotfi, Y., Mazel, D., Faruque, S. M., Woodgate, R., Waldor, M. K. (2001) Molecular analysis of antibiotic resistance gene clusters in Vibrio cholerae O139 and O1 SXT constins. Antimicrob Agents Chemother 45, 2991–3000.

44.	Sørum, H., Roberts, M. C., Crosa, J. H. (1992) Identification and cloning of a tetracycline resistance gene from the fish pathogen Vibrio salmonicida. Antimicrob Agents Chemother 36, 611–615.

45.	Szekeres, S., Dauti, M., Wilde, C., Mazel, D., Rowe-Magnus, D. A. (2007) Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection. Mol Microbiol 63, 1588–1605.

46.	Biskri, L., Bouvier, M., Guérout, A.-M., Boisnard, S., Mazel, D. (2005) Comparative study of class 1 integron and Vibrio cholerae superintegron integrase activities. J Bacteriol 187, 1740–1750.

47.	Vaisvila, R., Morgan, R. D., Posfai, J., Raleigh, E. A. (2001) Discovery and distribution of super-integrons among Pseudomonads. Mol Microbiol 42, 587–601.

48.	Holmes, A. J., Holley, M. P., Mahon, A., Nield, B., Gillings, M., Stokes, H. W. (2003) Recombination activity of a distinctive integron-gene cassette system associated with Pseudomonas stutzeri populations in soil. J Bacteriol 185, 918–928.

49.	Engelberg-Kulka, H., Glaser, G. (1999) Addiction modules and programmed cell death and antideath in bacteria cultures. Ann Rev Microbiol 53, 43–70.

50.	Prakash, D. P., Gerdes, K. (2005) Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucl Acids Res 33, 966–976.

51.	Labbate, M., Boucher, Y., Joss, M. J., Michael, C. A., Gillings, M. R., Stokes, H. W. (2007) Use of chromosomal integron arrays as a phylogenetic typing system for Vibrio cholerae pandemic strains. Microbiology 153, 1488–1498.

52.	Rowe-Magnus, D. A., Guerout, A.-M., Biskri, L., Bouige, P., Mazel, D. (2003) Comparative analysis of superintegrons: Engineering extensive genetic diversity in the Vibrionaceae. Genome Res 13, 428–442.

53.	Gillings, M. R., Holley, M. P., Stokes, H. W., Holmes, A. J. (2005) Integrons in Xanthomonas: A source of species genome diversity. Proc Nat Acad Sci U S A 102, 4419–4424.

54.	Coleman, N., Tetu, S., Wilson, N., Holmes, A. (2004) An unusual integron in Treponema denticola. Microbiology 150, 3524–3526.

55.	Demarre, G., Frumerie, C., Gopaul, D. N., Mazel, D. (2007) Identification of key structural determinants of the IntI1 integron integrase that influence attC × attI1 recombination efficiency. Nucl Acids Res 35, 6475–6489.

56.	Hall, R. M., Brookes, D. E., Stokes, H. W. (1991) Site-specific insertion of genes into integrons: role of the 59-base element and determination of the recombination cross-over point. Mol Microbiol 5, 1941–1959.

57.	Gravel, A., Messier, N., Roy, P. H. (1998) Point mutations in the integron integrase IntI1 that affect recombination and/or substrate recognition. J Bacteriol 180, 5437–5442.

58.	Melano, R. G., Petroni, A., Garutti, A., Saka, H., A, Mange, L., Pasterán, F., Rapoport, M., Rossi, A., Galas, M. (2002) New carbenicillin-hydrolyzing ×-lactamase (CARB-7) from Vibrio cholerae non-O1, non-0139 strains encoded by the VCR region of the V. cholerae genome. Antimicrob Agents Chemother 46, 2162–2168.

59.	Petroni, A., Melano, R. G., Saka, H., A, Garutti, A., Mange, L., Pasterán, F., Rapoport, M., Miranda, M., Faccone, D., Rossi, A., Hoffman, P. S., Galas, M. F. (2004) CARB-9, a carbenicillinase encoded in the VCR region of Vibrio cholerae non-01, non-0139 belongs to a family of cassette-encoded ×-lactamases. Antimicrob Agents Chemother 48, 4042–4046.

60.	Rowe-Magnus, D. A., Guerout, A.-M., Mazel, D. (2002) Bacterial resistance evolution by recruitment of super-integron gene cassettes. Mol Microbiol 43, 1657–1669.

61.	Recchia, G. D., Hall, R. M. (1997) Origins of the mobile gene cassettes found in integrons. Trends Microbiol 5, 389–394.

62.	Boucher, Y., Nesbo, C., Joss, M., Robinson, A., Mabbutt, B., Gillings, M., Doolittle, W. F., Stokes, H. (2006) Recovery and evolutionary analysis of complete integron gene cassette arrays from Vibrio. BMC Evol Biol 6, 3.

63.	Centrón, D., Roy, P. H. (2002) Presence of a group II intron in a multiresistant Serratia marcescens strain that harbors three integrons and a novel gene fusion. Antimicrob Agents Chemother 46, 1402–1409.

64.	Léon, G., Roy, P. H. (2003) Excision and integration of cassettes by an integron integrase of Nitrosomonas europaea. J Bacteriol 185, 2036–2041.

65.	Dai, L., Zimmerly, S. (2002) Compilation and analysis of group II intron insertions in bacterial genomes: evidence for retroelement behaviour. Nucl Acids Res 30, 1091–1102.

66.	Sunde, M. (2005) Class 1 integron with a group II intron detected in an Escherichia coli strain from a free-range reindeer. Antimicrob Agents Chemother 49, 2512–2514.

67.	Michael, C. A., Gillings, M. R., Holmes, A. J., Hughes, L., Andrew, N. R., P, H. M., Stokes, H. W. (2004) Mobile gene cassettes: a fundamental resource for bacterial evolution. Am Nat 164, 1–12.

68.	Ogawa, A., Takeda, T. (1993) The gene encoding the heat-stable enterotoxin of Vibrio cholerae is flanked by 123-bp direct repeats. Microbiol Immunol 37, 607–616.

69.	Franzon, V., L, Barker, A., Manning, P. (1993) Nucleotide sequence encoding the mannose-fucose-resistant hemagglutinin of Vibrio cholerae O1 and construction of a mutant. Infect Immun 61, 3032–3037.

70.	Barker, A., Clark, C. A. (1994) Identification of VCR, a repeated sequence associated with a locus encoding a hemagglutinin in Vibrio cholerae O1. J Bacteriol 176, 5450–5458.

71.	Barker, A., Manning, P. A. (1997) VlpA of Vibrio cholerae O1: the first bacterial member of the alpha 2-microglobulin lipocalin superfamily. Microbiology 143, 1805–1813.

72.	Kim, Y. R., Lee, S. E., Kim, C. M., Kim, S. Y., Shin, E. K., Shin, D. H., Chung, S. S., Choy, H. E., Progulske-Fox, A., Hillman, J. D., Handfield, M., Rhee, J. H. (2003) Characterization and pathogenic significance of Vibrio vulnificus antigens preferentially expressed in septicemic patients. Infect Immun 71, 5461–5471.

73.	Lee, J. H., Yang, S.-T., Rho, S.-H., Im, Y. J., Kim, S. Y., Kim, Y. R., Kim, M.-K., Kang, G. B., Kim, J. I., Rhee, J. H., Eom, S. H. (2006) Crystal structure and functional studies reveal that PAS factor from Vibrio vulnificus is a novel member of the Saposin-fold family. J Mol Biol 355, 491–500.

74.	Robinson, A., Guilfoyle, A. P., Harrop, S. J., Boucher, Y., Stokes, H. W., Curmi, P. M., Mabbutt, B. C. (2007) A putative house-cleaning enzyme encoded within an integron array: 1.8 Å crystal structure defines a new MazG subtype. Mol Microbiol 66, 610–621.

75.	Elsaied, H., Stokes, H. W., Nakamura, T., Kitamura, K., Fuse, H., Maruyama, A. (2001) Novel and diverse integron integrase genes and integron-like gene cassettes are prevalent in deep-sea hydrothermal vents. Environ Microbiol 9, 2298–2312.

76.	Nemergut, D. R., Martin, A. P., Schmidt, S. K. (2004) Integron diversity in heavy-metal-contaminated mine tailings and inferences about integron evolution. Appl Environ Microbiol 70, 1160–1168.

77.	Hayward, A. C. (1993) The Hosts of Xanthomonas. (J. G. Swings and E. L. Civerolo), Chapman & Hall, London, 1–17.

78.	Coleman, N. V., Holmes, A. J. (2005) The nativePseudomonas stutzeri strain Q chromosomal integron can capture and express cassette-associated genes. Microbiology 151, 1853–1864.

79.	Yildiz, F. H., Liu, X. S., Heydorn, A., Schoolnik, G. K. (2004) Molecular analysis of rugosity in a Vibrio cholerae O1 El Tor phase variant. Mol Microbiol 53, 497–515.

80.	Hughes, A. L. (2005) Gene duplication and the origin of novel proteins. Proc Natl Acad Sci U S A 102, 8791–8792.

81.	Nass, T., Mikami, Y., Imai, T., Poirel, L., Nordmann, P. (2001) Characterization of In53, a class 1 plasmid- and composite transposon-located integron of Escherichia coli which carries an unusual array of gene cassettes. J Bacteriol 183, 235–249.

82.	Tetu, S. G., Holmes, A. J. (2008) A family of insertion sequences that impacts integrons by specific targeting of gene cassette recombination sites, the IS1111-attc group. J Bacteriol 190, 4959–4970.

83.	Robinson, A., Wu, P. S., Harrop, S. J., Schaeffer, P. M., Dosztányi, Z., Gillings, M. R., Holmes, A. J., Nevalainen, K. M., Stokes, H. W., Otting, G., Dixon, N. E., Curmi, P. M., Mabbutt, B. C. (2005) Integron-associated mobile gene cassettes code for folded proteins: the structure of Bal32a, a new member of the adaptable alpha β barrel family. J Mol Biol 346, 1229–1241.

84.	Nield, B. S., Willows, R. D., Torda, A. E., Gillings, M. R., Holmes, A. J., Nevalainen, K. M. H., Stokes, H. W., Mabbutt, B. C. (2004) New enzymes from environmental cassette arrays: Functional attributes of a phosphotransferase and an RNA-methyltransferase. Protein Sci 13, 1651–1659.

85.	Cameron, F. H., Groot Obbink, D. J., Ackerman, V. P., Hall, R. M. (1986) Nucleotide sequence of the AAD(2″) aminoglycoside adenyltransferase determinant aadB. Evolutionary relationship of this region with those surrounding aadA in R538-1 and dhfrII in R388. Nucl Acids Res 14, 8625– 8635.

86.	Rowe-Magnus, D. A., Mazel, D. (1999) Resistance gene capture. Curr Opin Microbiol 2, 483–488.

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