Biopolym. Cell. 2004; 20(5):388-397.
Integrons as a key tool in bacteria evolution
1Kozyrovska N. O.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680


The integron/gene cassette system is a relatively simple structure, and it is linked to the mobile genetic elements pool that serves bacteria for their accommodation and survival in the changeable environment. The properties of integrons and gene cassettes indicate that these elements play a role in both adaptation to permanently changing environmental conditions and formation of the prokaryotic metagenome that is a resource for gene dissemination and evolution of bacteria. The diversity of integrons and cassette associated genes, an ancestry for integrons, and their spread are reviewed.


[1] Ochman H, Moran NA. Genes lost and genes found: evolution of bacterial pathogenesis and symbiosis. Science. 2001;292(5519):1096-9.
[2] Calcutt MJ, Lewis MS, Wise KS. Molecular genetic analysis of ICEF, an integrative conjugal element that is present as a repetitive sequence in the chromosome of Mycoplasma fermentans PG18. J Bacteriol. 2002;184(24):6929-41.
[3] Nunes LR, Rosato YB, Muto NH, Yanai GM, da Silva VS, Leite DB, Goncalves ER, de Souza AA, Coletta-Filho HD, Machado MA, Lopes SA, de Oliveira RC. Microarray analyses of Xylella fastidiosa provide evidence of coordinated transcription control of laterally transferred elements. Genome Res. 2003;13(4):570-8.
[4] Kordyum VA Evolution and biosfera. Kiev: Naukova Dumka,1982. 260 p.
[5] Lopez-Garcia P, Brochier C, Moreira D, Rodriguez-Valera F. Comparative analysis of a genome fragment of an uncultivated mesopelagic crenarchaeote reveals multiple horizontal gene transfers. Environ Microbiol. 2004;6(1):19-34.
[6] Collis CM, Hall RM. Gene cassettes from the insert region of integrons are excised as covalently closed circles. Mol Microbiol. 1992;6(19):2875-85.
[7] Collis CM, Hall RM. Site-specific deletion and rearrangement of integron insert genes catalyzed by the integron DNA integrase. J Bacteriol. 1992;174(5):1574-85.
[8] Collis CM, Grammaticopoulos G, Briton J, Stokes HW, Hall RM. Site-specific insertion of gene cassettes into integrons. Mol Microbiol. 1993;9(1):41-52.
[9] Stokes HW, Hall RM. A novel family of potentially mobile DNA elements encoding site-specific gene-integration functions: integrons. Mol Microbiol. 1989;3(12):1669-83.
[10] Collis CM, Recchia GD, Kim MJ, Stokes HW, Hall RM. Efficiency of recombination reactions catalyzed by class 1 integron integrase IntI1. J Bacteriol. 2001;183(8):2535-42.
[11] Zhao S, Qaiyumi S, Friedman S, Singh R, Foley SL, White DG, McDermott PF, Donkar T, Bolin C, Munro S, Baron EJ, Walker RD. Characterization of Salmonella enterica serotype newport isolated from humans and food animals. J Clin Microbiol. 2003;41(12):5366-71.
[12] DeLappe N, O'Halloran F, Fanning S, Corbett-Feeney G, Cheasty T, Cormican M. Antimicrobial resistance and genetic diversity of Shigella sonnei isolates from western Ireland, an area of low incidence of infection. J Clin Microbiol. 2003;41(5):1919-24.
[13] Poirel L, Heritier C, Toun V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004;48(1):15-22.
[14] Bagattini M, Crispino M, Gentile F, Barretta E, Schiavone D, Boccia MC, Triassi M, Zarrilli R. A nosocomial outbreak of Serratia marcescens producing inducible Amp C-type beta-lactamase enzyme and carrying antimicrobial resistance genes within a class 1 integron. J Hosp Infect. 2004;56(1):29-36.
[15] Collis CM, Hall RM. Expression of antibiotic resistance genes in the integrated cassettes of integrons. Antimicrob Agents Chemother. 1995;39(1):155-62.
[16] Levesque C, Brassard S, Lapointe J, Roy PH. Diversity and relative strength of tandem promoters for the antibiotic-resistance genes of several integrons. Gene. 1994;142(1):49-54.
[17] Hall RM, Brookes DE, Stokes HW. Site-specific insertion of genes into integrons: role of the 59-base element and determination of the recombination cross-over point. Mol Microbiol. 1991;5(8):1941-59.
[18] Recchia GD, Hall RM. Origins of the mobile gene cassettes found in integrons. Trends Microbiol. 1997;5(10):389-94.
[19] Cameron FH, Groot Obbink DJ, Ackerman VP, Hall RM. Nucleotide sequence of the AAD(2'') aminoglycoside adenylyltransferase determinant aadB. Evolutionary relationship of this region with those surrounding aadA in R538-1 and dhfrII in R388. Nucleic Acids Res. 1986;14(21):8625-35.
[20] Bissonnette L, Champetier S, Buisson JP, Roy PH. Characterization of the nonenzymatic chloramphenicol resistance (cmlA) gene of the In4 integron of Tn1696: similarity of the product to transmembrane transport proteins. J Bacteriol. 1991;173(14):4493-502.
[21] Biskri L, Mazel D. Erythromycin esterase gene ere(A) is located in a functional gene cassette in an unusual class 2 integron. Antimicrob Agents Chemother. 2003;47(10):3326-31.
[22] Bunny KL, Hall RM, Stokes HW. New mobile gene cassettes containing an aminoglycoside resistance gene, aacA7, and a chloramphenicol resistance gene, catB3, in an integron in pBWH301. Antimicrob Agents Chemother. 1995;39(3):686-93.
[23] Peters ED, Leverstein-van Hall MA, Box AT, Verhoef J, Fluit AC. Novel gene cassettes and integrons. Antimicrob Agents Chemother. 2001;45(10):2961-4.
[24] Stokes HW, Holmes AJ, Nield BS, Holley MP, Nevalainen KM, Mabbutt BC, Gillings MR. Gene cassette PCR: sequence-independent recovery of entire genes from environmental DNA. Appl Environ Microbiol. 2001;67(11):5240-6.
[25] Nield BS, Holmes AJ, Gillings MR, Recchia GD, Mabbutt BC, Nevalainen KM, Stokes HW. Recovery of new integron classes from environmental DNA. FEMS Microbiol Lett. 2001;195(1):59-65.
[26] Stokes HW, O'Gorman DB, Recchia GD, Parsekhian M, Hall RM. Structure and function of 59-base element recombination sites associated with mobile gene cassettes.
[27] Partridge SR, Brown HJ, Hall RM. Characterization and movement of the class 1 integron known as Tn2521 and Tn1405. Antimicrob Agents Chemother. 2002;46(5):1288-94.
[28] Esposito D, Scocca JJ. The integrase family of tyrosine recombinases: evolution of a conserved active site domain. Nucleic Acids Res. 1997;25(18):3605-14.
[29] Ouellette M, Roy PH. Homology of ORFs from Tn2603 and from R46 to site-specific recombinases. Nucleic Acids Res. 1987;15(23):10055.
[30] Pargellis CA, Nunes-D?by SE, de Vargas LM, Landy A. Suicide recombination substrates yield covalent lambda integrase-DNA complexes and lead to identification of the active site tyrosine. J Biol Chem. 1988;263(16):7678-85.
[31] Messier N, Roy PH. Integron integrases possess a unique additional domain necessary for activity. J Bacteriol. 2001;183(22):6699-706.
[32] Holmes AJ, Holley MP, Mahon A, Nield B, Gillings M, Stokes HW. Recombination activity of a distinctive integron-gene cassette system associated with Pseudomonas stutzeri populations in soil. J Bacteriol. 2003;185(3):918-28.
[33] Drouin F, Melan?on J, Roy PH. The IntI-like tyrosine recombinase of Shewanella oneidensis is active as an integron integrase. J Bacteriol. 2002;184(6):1811-5.
[34] Leon G, Roy PH. Excision and integration of cassettes by an integron integrase of Nitrosomonas europaea. J Bacteriol. 2003;185(6):2036-41.
[35] Hochhut B, Lotfi Y, Mazel D, Faruque SM, Woodgate R, Waldor MK. Molecular analysis of antibiotic resistance gene clusters in vibrio cholerae O139 and O1 SXT constins. Antimicrob Agents Chemother. 2001;45(11):2991-3000.
[36] Radstrom P, Skold O, Swedberg G, Flensburg J, Roy PH, Sundstrom L. Transposon Tn5090 of plasmid R751, which carries an integron, is related to Tn7, Mu, and the retroelements. J Bacteriol. 1994;176(11):3257-68.
[37] Kamali-Moghaddam M, Sundstrom L. Transposon targeting determined by resolvase. FEMS Microbiol Lett. 2000;186(1):55-9.
[38] Brown HJ, Stokes HW, Hall RM. The integrons In0, In2, and In5 are defective transposon derivatives. J Bacteriol. 1996;178(15):4429-37.
[39] Hall RM, Brown HJ, Brookes DE, Stokes HW. Integrons found in different locations have identical 5' ends but variable 3' ends. J Bacteriol. 1994;176(20):6286-94.
[40] Paulsen IT, Littlejohn TG, Radstrom P, Sundstrom L, Sk?ld O, Swedberg G, Skurray RA. The 3' conserved segment of integrons contains a gene associated with multidrug resistance to antiseptics and disinfectants. Antimicrob Agents Chemother. 1993;37(4):761-8.
[41] Sundstrom L., Radstrom P., Swedberg G., Skold O. Site-specific recombination promotes linkage between trimethoprim- and sulfonamide resistance genes. Sequence characterization of dhfrV and suII and a recombination active locus of Tn21. Mol Gen Genet. 1988;213 (2-3):191-201.
[42] Hall RM, Vockler C. The region of the IncN plasmid R46 coding for resistance to beta-lactam antibiotics, streptomycin/spectinomycin and sulphonamides is closely related to antibiotic resistance segments found in IncW plasmids and in Tn21-like transposons. Nucleic Acids Res. 1987;15(18):7491-501.
[43] Stokes HW, Hall RM. A novel family of potentially mobile DNA elements encoding site-specific gene-integration functions: integrons. Mol Microbiol. 1989;3(12):1669-83.
[44] Fling ME, Richards C. The nucleotide sequence of the trimethoprim-resistant dihydrofolate reductase gene harbored by Tn7. Nucleic Acids Res. 1983;11(15):5147-58.
[45] Miko A, Pries K, Schroeter A, Helmuth R. Multiple-drug resistance in D-tartrate-positive Salmonella enterica serovar paratyphi B isolates from poultry is mediated by class 2 integrons inserted into the bacterial chromosome. Antimicrob Agents Chemother. 2003;47(11):3640-3.
[46] Arakawa Y, Murakami M, Suzuki K, Ito H, Wacharotayankun R, Ohsuka S, Kato N, Ohta M. A novel integron-like element carrying the metallo-beta-lactamase gene blaIMP. Antimicrob Agents Chemother. 1995;39(7):1612-5.
[47] Correia M, Boavida F, Grosso F, Salgado MJ, Lito LM, Cristino JM, Mendo S, Duarte A. Molecular characterization of a new class 3 integron in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2003;47(9):2838-43.
[48] Collis CM, Kim MJ, Partridge SR, Stokes HW, Hall RM. Characterization of the class 3 integron and the site-specific recombination system it determines. J Bacteriol. 2002;184(11):3017-26.
[49] Ploy MC, Denis F, Courvalin P, Lambert T. Molecular characterization of integrons in Acinetobacter baumannii: description of a hybrid class 2 integron. Antimicrob Agents Chemother. 2000;44(10):2684-8.
[50] Waldor MK, Tschape H, Mekalanos JJ. A new type of conjugative transposon encodes resistance to sulfamethoxazole, trimethoprim, and streptomycin in Vibrio cholerae O139. J Bacteriol. 1996;178(14):4157-65.
[51] Clark CA, Purins L, Kaewrakon P, Manning PA. VCR repetitive sequence elements in the Vibrio cholerae chromosome constitute a mega-integron. Mol Microbiol. 1997;26(5):1137-8.
[52] Hall RM, Stokes HW. Integrons or super integrons? Microbiology. 2004;150(Pt 1):3-4.
[53] Holmes AJ, Gillings MR, Nield BS, Mabbutt BC, Nevalainen KM, Stokes HW. The gene cassette metagenome is a basic resource for bacterial genome evolution. Environ Microbiol. 2003;5(5):383-94.
[54] Rowe-Magnus DA, Guerout AM, Mazel D. Super-integrons. Res Microbiol. 1999;150(9-10):641-51.
[55] Mazel D, Dychinco B, Webb VA, Davies J. A distinctive class of integron in the Vibrio cholerae genome. Science. 1998;280(5363):605-8.
[56] Heidelberg JF, Eisen JA, Nelson WC, Clayton RA, Gwinn ML, Dodson RJ, Haft DH, Hickey EK, Peterson JD, Umayam L, Gill SR, Nelson KE, Read TD, et al. DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae. Nature. 2000;406(6795):477-83.
[57] Mazel D, Dychinco B, Webb VA, Davies J. Antibiotic resistance in the ECOR collection: integrons and identification of a novel aad gene. Antimicrob Agents Chemother. 2000;44(6):1568-74.
[58] Rowe-Magnus DA, Guerout AM, Ploncard P, Dychinco B, Davies J, Mazel D. The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons. Proc Natl Acad Sci U S A. 2001;98(2):652-7.
[59] Rowe-Magnus DA, Guerout AM, Biskri L, Bouige P, Mazel D. Comparative analysis of superintegrons: engineering extensive genetic diversity in the Vibrionaceae. Genome Res. 2003;13(3):428-42.
[60] Engelberg-Kulka H, Glaser G. Addiction modules and programmed cell death and antideath in bacterial cultures. Annu Rev Microbiol. 1999;53:43-70.
[61] Santos Sierra S, Giraldo R, Diaz Orejas R. Functional interactions between chpB and parD, two homologous conditional killer systems found in the Escherichia coli chromosome and in plasmid R1. FEMS Microbiol Lett. 1998;168(1):51-8.
[62] Kobayashi I, Nobusato A, Kobayashi-Takahashi N, Uchiyama I. Shaping the genome--restriction-modification systems as mobile genetic elements. Curr Opin Genet Dev. 1999;9(6):649-56.
[63] Vaisvila R, Morgan RD, Posfai J, Raleigh EA. Discovery and distribution of super-integrons among pseudomonads. Mol Microbiol. 2001;42(3):587-601.
[64] Liebert CA, Hall RM, Summers AO. Transposon Tn21, flagship of the floating genome. Microbiol Mol Biol Rev. 1999;63(3):507-22.
[65] Naas T, Mikami Y, Imai T, Poirel L, Nordmann P. 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. 2001;183(1):235-49.
[66] Klockgether J, Reva O, Larbig K, Tummler B. Sequence analysis of the mobile genome island pKLC102 of Pseudomonas aeruginosa C. J Bacteriol. 2004;186(2):518-34.
[67] Boyd D, Cloeckaert A, Chaslus-Dancla E, Mulvey MR. Characterization of variant Salmonella genomic island 1 multidrug resistance regions from serovars Typhimurium DT104 and Agona. Antimicrob Agents Chemother. 2002;46(6):1714-22.
[68] Dalsgaard A, Forslund A, Serichantalergs O, Sandvang D. Distribution and content of class 1 integrons in different Vibrio cholerae O-serotype strains isolated in Thailand. Antimicrob Agents Chemother. 2000;44(5):1315-21.
[69] Centron D, Roy PH. Presence of a group II intron in a multiresistant Serratia marcescens strain that harbors three integrons and a novel gene fusion. Antimicrob Agents Chemother. 2002;46(5):1402-9.
[70] Bass L, Liebert CA, Lee MD, Summers AO, White DG, Thayer SG, Maurer JJ. Incidence and characterization of integrons, genetic elements mediating multiple-drug resistance, in avian Escherichia coli. Antimicrob Agents Chemother. 1999;43(12):2925-9.
[71] Sunde M, Sorum H. Self-transmissible multidrug resistance plasmids in Escherichia coli of the normal intestinal flora of healthy swine. Microb Drug Resist. 2001 Summer;7(2):191-6.
[72] Roe MT, Vega E, Pillai SD. Antimicrobial resistance markers of class 1 and class 2 integron-bearing Escherichia coli from irrigation water and sediments. Emerg Infect Dis. 2003;9(7):822-6.
[73] Yu HS, Lee JC, Kang HY, Ro DW, Chung JY, Jeong YS, Tae SH, Choi CH, Lee EY, Seol SY, Lee YC, Cho DT. Changes in gene cassettes of class 1 integrons among Escherichia coli isolates from urine specimens collected in Korea during the last two decades. J Clin Microbiol. 2003;41(12):5429-33.
[74] Shibata N, Doi Y, Yamane K, Yagi T, Kurokawa H, Shibayama K, Kato H, Kai K, Arakawa Y. PCR typing of genetic determinants for metallo-beta-lactamases and integrases carried by gram-negative bacteria isolated in Japan, with focus on the class 3 integron. J Clin Microbiol. 2003;41(12):5407-13.
[75] Goldstein C, Lee MD, Sanchez S, Hudson C, Phillips B, Register B, Grady M, Liebert C, Summers AO, White DG, Maurer JJ. Incidence of class 1 and 2 integrases in clinical and commensal bacteria from livestock, companion animals, and exotics. Antimicrob Agents Chemother. 2001;45(3):723-6.
[76] Oh JY, Yu HS, Kim SK, Seol SY, Cho DT, Lee JC. Changes in patterns of antimicrobial susceptibility and integron carriage among Shigella sonnei isolates from southwestern Korea during epidemic periods. J Clin Microbiol. 2003;41(1):421-3.
[77] Ploy MC, Chainier D, Tran Thi NH, Poilane I, Cruaud P, Denis F, Collignon A, Lambert T. Integron-associated antibiotic resistance in Salmonella enterica serovar typhi from Asia. Antimicrob Agents Chemother. 2003;47(4):1427-9.
[78] Poirel L, Heritier C, Tolun V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004;48(1):15-22.
[79] Soto SM, Lobato MJ, Mendoza MC. Class 1 integron-borne gene cassettes in multidrug-resistant Yersinia enterocolitica strains of different phenotypic and genetic types. Antimicrob Agents Chemother. 2003;47(1):421-6.
[80] Laraki N1, Galleni M, Thamm I, Riccio ML, Amicosante G, Fr?re JM, Rossolini GM. Structure of In31, a blaIMP-containing Pseudomonas aeruginosa integron phyletically related to In5, which carries an unusual array of gene cassettes. Antimicrob Agents Chemother. 1999;43(4):890-901.
[81] Lee K, Lim JB, Yum JH, Yong D, Chong Y, Kim JM, Livermore DM. bla(VIM-2) cassette-containing novel integrons in metallo-beta-lactamase-producing Pseudomonas aeruginosa and Pseudomonas putida isolates disseminated in a Korean hospital. Antimicrob Agents Chemother. 2002;46(4):1053-8.
[82] Docquier JD, Riccio ML, Mugnaioli C, Luzzaro F, Endimiani A, Toniolo A, Amicosante G, Rossolini GM. IMP-12, a new plasmid-encoded metallo-beta-lactamase from a Pseudomonas putida clinical isolate. Antimicrob Agents Chemother. 2003;47(5):1522-8.
[83] Schmitz FJ, Hafner D, Geisel R, Follmann P, Kirschke C, Verhoef J, Kohrer K, Fluit AC. Increased prevalence of class I integrons in Escherichia coli, Klebsiella species, and Enterobacter species isolates over a 7-year period in a German university hospital. J Clin Microbiol. 2001;39(10):3724-6.
[84] Schluter A1, Heuer H, Szczepanowski R, Forney LJ, Thomas CM, Puhler A, Top EM. The 64 508 bp IncP-1beta antibiotic multiresistance plasmid pB10 isolated from a waste-water treatment plant provides evidence for recombination between members of different branches of the IncP-1beta group. Microbiology. 2003;149(Pt 11):3139-53.