Integrons: Past, Present, and Future

SUMMARY Integrons are versatile gene acquisition systems commonly found in bacterial genomes. They are ancient elements that are a hot spot for genomic complexity, generating phenotypic diversity and shaping adaptive responses. In recent times, they have had a major role in the acquisition, expression, and dissemination of antibiotic resistance genes. Assessing the ongoing threats posed by integrons requires an understanding of their origins and evolutionary history. This review examines the functions and activities of integrons before the antibiotic era. It shows how antibiotic use selected particular integrons from among the environmental pool of these elements, such that integrons carrying resistance genes are now present in the majority of Gram-negative pathogens. Finally, it examines the potential consequences of widespread pollution with the novel integrons that have been assembled via the agency of human antibiotic use and speculates on the potential uses of integrons as platforms for biotechnology.

[1]  M. Arabi,et al.  Identification of antibiotic-resistance-gene molecular signatures suitable as tracers of pristine river, urban, and agricultural sources. , 2010, Environmental science & technology.

[2]  H. Stokes,et al.  Genetic Context and Structural Diversity of Class 1 Integrons from Human Commensal Bacteria in a Hospital Intensive Care Unit , 2011, Antimicrobial Agents and Chemotherapy.

[3]  Jianying Hu,et al.  Antibiotic-resistance profile in environmental bacteria isolated from penicillin production wastewater treatment plant and the receiving river. , 2009, Environmental microbiology.

[4]  P. Keen,et al.  Tracking Change: A Look at the Ecological Footprint of Antibiotics and Antimicrobial Resistance , 2013, Antibiotics.

[5]  C. Médigue,et al.  Genome sequence of Vibrio splendidus: an abundant planctonic marine species with a large genotypic diversity. , 2009, Environmental microbiology.

[6]  Olivier Tenaillon,et al.  The population genetics of commensal Escherichia coli , 2010, Nature Reviews Microbiology.

[7]  Charles W. Knapp,et al.  Evidence of increasing antibiotic resistance gene abundances in archived soils since 1940. , 2010, Environmental science & technology.

[8]  R M Stuetz,et al.  Fate of antibiotics during municipal water recycling treatment processes. , 2010, Water research.

[9]  E. Wellington,et al.  Incidence of Class 1 Integrons in a Quaternary Ammonium Compound-Polluted Environment , 2005, Antimicrobial Agents and Chemotherapy.

[10]  P. Campbell,et al.  Outbreak of angular leaf spot, caused by Xanthomonas fragariae, in a Queensland strawberry germplasm collection , 2011, Australasian Plant Pathology.

[11]  H. Stokes,et al.  Class 1 integrons in benthic bacterial communities: abundance, association with Tn402-like transposition modules and evidence for coselection with heavy-metal resistance. , 2010, FEMS microbiology ecology.

[12]  Ramunas Stepanauskas,et al.  Co-selection of antibiotic and metal resistance. , 2006, Trends in microbiology.

[13]  C. M. Collis,et al.  Integron‐encoded IntI integrases preferentially recognize the adjacent cognate attI site in recombination with a 59‐be site , 2002, Molecular microbiology.

[14]  D. Mazel,et al.  Inverse Correlation between Promoter Strength and Excision Activity in Class 1 Integrons , 2010, PLoS genetics.

[15]  R. Fanelli,et al.  Source, occurrence and fate of antibiotics in the Italian aquatic environment. , 2010, Journal of hazardous materials.

[16]  M. S. Ramírez,et al.  Novel Insights about Class 2 Integrons from Experimental and Genomic Epidemiology , 2009, Antimicrobial Agents and Chemotherapy.

[17]  Gan Zhang,et al.  Occurrence and distribution of antibiotics in the Beibu Gulf, China: impacts of river discharge and aquaculture activities. , 2012, Marine environmental research.

[18]  Heike Schmitt,et al.  Antibiotic resistance gene spread due to manure application on agricultural fields. , 2011, Current opinion in microbiology.

[19]  Yu Miao,et al.  Metagenomic Profiling of Antibiotic Resistance Genes and Mobile Genetic Elements in a Tannery Wastewater Treatment Plant , 2013, PloS one.

[20]  H. A. Saka,et al.  New Carbenicillin-Hydrolyzing β-Lactamase (CARB-7) from Vibrio cholerae Non-O1, Non-O139 Strains Encoded by the VCR Region of the V. cholerae Genome , 2002, Antimicrobial Agents and Chemotherapy.

[21]  P. Manning,et al.  VlpA of Vibrio cholerae 01 : the first bacterial member of the a ,-microglobulin lipocalin superfamily , 2008 .

[22]  K. Smalla,et al.  Wastewater bacterial communities bring together broad-host range plasmids, integrons and a wide diversity of uncharacterized gene cassettes. , 2010, Research in microbiology.

[23]  R M Hall,et al.  Binding of the purified integron DNA integrase IntI1 to integron‐ and cassette‐associated recombination sites , 1998, Molecular microbiology.

[24]  M. Gillings,et al.  Integrons in Xanthomonas: a source of species genome diversity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  S. Hardwick,et al.  Recovery of diverse genes for class 1 integron-integrases from environmental DNA samples. , 2008, FEMS microbiology letters.

[26]  J. Davies,et al.  Origins and Evolution of Antibiotic Resistance , 1996, Microbiology and Molecular Biology Reviews.

[27]  K. Gobius,et al.  Diverse class 2 integrons in bacteria from beef cattle sources. , 2006, The Journal of antimicrobial chemotherapy.

[28]  Michael J. Joss,et al.  Integron Gene Cassettes and Degradation of Compounds Associated with Industrial Waste: The Case of the Sydney Tar Ponds , 2009, PloS one.

[29]  D. Johnson,et al.  Redox Transformations of Iron at Extremely Low pH: Fundamental and Applied Aspects , 2012, Front. Microbio..

[30]  Samuel I. Miller,et al.  Evidence for Induction of Integron-Based Antibiotic Resistance by the SOS Response in a Clinical Setting , 2012, PLoS pathogens.

[31]  N. Coleman,et al.  Natural transformation with synthetic gene cassettes: new tools for integron research and biotechnology. , 2011, Microbiology.

[32]  I. Matic,et al.  Evolutionary significance of stress-induced mutagenesis in bacteria. , 2004, Trends in microbiology.

[33]  Y. Kamagata,et al.  Marine integrons containing novel integrase genes, attachment sites, attI, and associated gene cassettes in polluted sediments from Suez and Tokyo Bays , 2011, The ISME Journal.

[34]  M. A. Maldonado,et al.  Salmon Aquaculture and Antimicrobial Resistance in the Marine Environment , 2012, PloS one.

[35]  W. Doolittle,et al.  Integron-associated gene cassettes in Halifax Harbour: assessment of a mobile gene pool in marine sediments. , 2008, Environmental microbiology.

[36]  Y. Boucher,et al.  Structural genomics of the bacterial mobile metagenome: an overview. , 2008, Methods in molecular biology.

[37]  A. Holmes,et al.  The native Pseudomonas stutzeri strain Q chromosomal integron can capture and express cassette-associated genes. , 2005, Microbiology.

[38]  C. Baker-Austin,et al.  Aquatic systems: maintaining, mixing and mobilising antimicrobial resistance? , 2011, Trends in ecology & evolution.

[39]  P. Nordmann,et al.  A novel IncQ plasmid type harbouring a class 3 integron from Escherichia coli. , 2010, The Journal of antimicrobial chemotherapy.

[40]  J. Chun,et al.  Comparative genomics of clinical and environmental Vibrio mimicus , 2010, Proceedings of the National Academy of Sciences of the United States of America.

[41]  A. Carattoli,et al.  Population Structure and Resistance Genes in Antibiotic-Resistant Bacteria from a Remote Community with Minimal Antibiotic Exposure , 2006, Antimicrobial Agents and Chemotherapy.

[42]  R. Koczura,et al.  Multiresistant Enterobacteriaceae with class 1 and class 2 integrons in a municipal wastewater treatment plant. , 2012, Water research.

[43]  Y. Boucher,et al.  Use of chromosomal integron arrays as a phylogenetic typing system for Vibrio cholerae pandemic strains. , 2007, Microbiology.

[44]  Guy Tsafnat,et al.  RAC: Repository of Antibiotic resistance Cassettes , 2011, Database J. Biol. Databases Curation.

[45]  R M Hall,et al.  Site‐specific insertion of gene cassettes into integrons , 1993, Molecular microbiology.

[46]  A. Boxall,et al.  Impacts of anthropogenic activity on the ecology of class 1 integrons and integron-associated genes in the environment , 2011, The ISME Journal.

[47]  Qingquan Luo,et al.  Identification and Characterization of Integron-Mediated Antibiotic Resistance in the Phytopathogen Xanthomonas oryzae pv. oryzae , 2013, PloS one.

[48]  M. Sadowsky,et al.  Air-drying beds reduce the quantities of antibiotic resistance genes and class 1 integrons in residual municipal wastewater solids. , 2013, Environmental science & technology.

[49]  C. Loot,et al.  Replicative resolution of integron cassette insertion , 2012, Nucleic acids research.

[50]  P. H. Roy,et al.  DNA complexes obtained with the integron integrase IntI1 at the attI1 site. , 1998, Nucleic acids research.

[51]  I. Paulsen,et al.  The 3' conserved segment of integrons contains a gene associated with multidrug resistance to antiseptics and disinfectants , 1993, Antimicrobial Agents and Chemotherapy.

[52]  Heather K. Allen,et al.  Call of the wild: antibiotic resistance genes in natural environments , 2010, Nature Reviews Microbiology.

[53]  Gerard D. Wright Antibiotic Resistome: A Framework Linking the Clinic and the Environment , 2011 .

[54]  E. Gotuzzo,et al.  Antibiotic resistance in a very remote Amazonas community. , 2009, International journal of antimicrobial agents.

[55]  David Bikard,et al.  The synthetic integron: an in vivo genetic shuffling device , 2010, Nucleic acids research.

[56]  Alexander Goesmann,et al.  Genetic diversity and composition of a plasmid metagenome from a wastewater treatment plant. , 2008, Journal of biotechnology.

[57]  M. Gillings,et al.  Evidence for dynamic exchange of qac gene cassettes between class 1 integrons and other integrons in freshwater biofilms. , 2009, FEMS microbiology letters.

[58]  Sally R. Partridge,et al.  Characterization of the Class 3 Integron and the Site-Specific Recombination System It Determines , 2002, Journal of bacteriology.

[59]  Hong Chen,et al.  Abundance and persistence of antibiotic resistance genes in livestock farms: a comprehensive investigation in eastern China. , 2013, Environment international.

[60]  K. Nielsen,et al.  Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects , 2012, PLoS pathogens.

[61]  M. Labbate,et al.  Recovery of a Functional Class 2 Integron from an Escherichia coli Strain Mediating a Urinary Tract Infection , 2008, Antimicrobial Agents and Chemotherapy.

[62]  R. Siebeling,et al.  Identification of Genetic Loci Required for Capsular Expression in Vibrio vulnificus , 2003, Infection and Immunity.

[63]  R. Hall,et al.  Transposon Tn21, Flagship of the Floating Genome , 1999, Microbiology and Molecular Biology Reviews.

[64]  S. Partridge,et al.  Analysis of antibiotic resistance regions in Gram-negative bacteria. , 2011, FEMS microbiology reviews.

[65]  D. Mazel,et al.  Comparative Study of Class 1 Integron and Vibrio cholerae Superintegron Integrase Activities , 2005, Journal of bacteriology.

[66]  J. Maurer,et al.  Gram-positive bacteria are a major reservoir of Class 1 antibiotic resistance integrons in poultry litter. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[67]  J. Davies,et al.  Molecular Characterization of Class 3 Integrons from Delftia spp , 2007, Journal of bacteriology.

[68]  Hong Chen,et al.  Effects of advanced treatment systems on the removal of antibiotic resistance genes in wastewater treatment plants from Hangzhou, China. , 2013, Environmental science & technology.

[69]  R. Kucherlapati,et al.  Genomic characterization of non-O1, non-O139 Vibrio cholerae reveals genes for a type III secretion system. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[70]  Ji-Liang Tang,et al.  sRNA-Xcc1, an integron-encoded transposon- and plasmid-transferred trans-acting sRNA, is under the positive control of the key virulence regulators HrpG and HrpX of Xanthomonas campestris pathovar campestris , 2011, RNA biology.

[71]  A. Russell Introduction of biocides into clinical practice and the impact on antibiotic‐resistant bacteria , 2002, Journal of applied microbiology.

[72]  Enrico W. Coiera,et al.  Context-driven discovery of gene cassettes in mobile integrons using a computational grammar , 2009, BMC Bioinformatics.

[73]  M. Gillings,et al.  Proposal of Xanthomonas translucens pv. pistaciae pv. nov., pathogenic to pistachio (Pistacia vera). , 2009, Systematic and applied microbiology.

[74]  Amy Pruden,et al.  Antibiotic resistance genes as emerging contaminants: studies in northern Colorado. , 2006, Environmental science & technology.

[75]  R M Hall,et al.  Structure and function of 59‐base element recombination sites associated with mobile gene cassettes , 1997, Molecular microbiology.

[76]  A. Pühler,et al.  Genomics of IncP-1 antibiotic resistance plasmids isolated from wastewater treatment plants provides evidence for a widely accessible drug resistance gene pool. , 2007, FEMS microbiology reviews.

[77]  R. Woodgate,et al.  Molecular Analysis of Antibiotic Resistance Gene Clusters in Vibrio cholerae O139 and O1 SXT Constins , 2001, Antimicrobial Agents and Chemotherapy.

[78]  M. Gillings,et al.  Preclinical Class 1 Integron with a Complete Tn402-Like Transposition Module , 2010, Applied and Environmental Microbiology.

[79]  M. Gillings,et al.  Recovery of new integron classes from environmental DNA. , 2001, FEMS microbiology letters.

[80]  R. Hall,et al.  Transposons Tn1696 and Tn21and Their Integrons In4 and In2 Have Independent Origins , 2001, Antimicrobial Agents and Chemotherapy.

[81]  A. Vicente,et al.  Architecture of the superintegron in Vibrio cholerae: identification of core and unique genes , 2013, F1000Research.

[82]  P. McNamara,et al.  Tertiary-treated municipal wastewater is a significant point source of antibiotic resistance genes into Duluth-Superior Harbor. , 2011, Environmental science & technology.

[83]  Otto X. Cordero,et al.  Local Mobile Gene Pools Rapidly Cross Species Boundaries To Create Endemicity within Global Vibrio cholerae Populations , 2011, mBio.

[84]  Keiko Kitamura,et al.  Novel and diverse integron integrase genes and integron-like gene cassettes are prevalent in deep-sea hydrothermal vents. , 2007, Environmental microbiology.

[85]  S. Koike,et al.  Fate and transport of antibiotic residues and antibiotic resistance genes following land application of manure waste. , 2009, Journal of environmental quality.

[86]  Anna B. Rachlin,et al.  Cellular pathways controlling integron cassette site folding , 2010, The EMBO journal.

[87]  K. Smalla,et al.  Broad diversity of conjugative plasmids in integron-carrying bacteria from wastewater environments. , 2012, FEMS microbiology letters.

[88]  Yan Boucher,et al.  Integrons: mobilizable platforms that promote genetic diversity in bacteria. , 2007, Trends in microbiology.

[89]  P. H. Roy,et al.  Characterization of the nonenzymatic chloramphenicol resistance (cmlA) gene of the In4 integron of Tn1696: similarity of the product to transmembrane transport proteins , 1991, Journal of bacteriology.

[90]  Z. Baharoglu,et al.  Conjugative DNA Transfer Induces the Bacterial SOS Response and Promotes Antibiotic Resistance Development through Integron Activation , 2010, PLoS genetics.

[91]  K. Gerdes,et al.  Two higBA loci in the Vibrio cholerae superintegron encode mRNA cleaving enzymes and can stabilize plasmids , 2006, Molecular microbiology.

[92]  K. M. Helena Nevalainen,et al.  Gene Cassette PCR: Sequence-Independent Recovery of Entire Genes from Environmental DNA , 2001, Applied and Environmental Microbiology.

[93]  E. C. Teixeira,et al.  Comparison of the genomes of two Xanthomonas pathogens with differing host specificities , 2002, Nature.

[94]  R M Hall,et al.  Mobile gene cassettes and integrons: capture and spread of genes by site‐specific recombination , 1995, Molecular microbiology.

[95]  Gan Zhang,et al.  Antibiotics in the offshore waters of the Bohai Sea and the Yellow Sea in China: occurrence, distribution and ecological risks. , 2013, Environmental pollution.

[96]  Shih-Feng Tsai,et al.  Comparative genome analysis of Vibrio vulnificus, a marine pathogen. , 2003, Genome research.

[97]  R. Hall,et al.  Sequence analysis of the inducible chloramphenicol resistance determinant in the Tn1696 integron suggests regulation by translational attenuation. , 1991, Plasmid.

[98]  T. Berendonk,et al.  Heavy metal driven co-selection of antibiotic resistance in soil and water bodies impacted by agriculture and aquaculture , 2012, Front. Microbio..

[99]  R. Koczura,et al.  Antimicrobial resistance of integron-harboring Escherichia coli isolates from clinical samples, wastewater treatment plant and river water. , 2012, The Science of the total environment.

[100]  P. Manning,et al.  The Vibrio cholerae O1 chromosomal integron. , 2000, Microbiology.

[101]  Z. Baharoglu,et al.  Vibrio cholerae Triggers SOS and Mutagenesis in Response to a Wide Range of Antibiotics: a Route towards Multiresistance , 2011, Antimicrobial Agents and Chemotherapy.

[102]  H. V. Gelder The Netherlands , 2004, Constitutions of Europe (2 vols.).

[103]  Stefan Wuertz,et al.  Studying plasmid horizontal transfer in situ: a critical review , 2005, Nature Reviews Microbiology.

[104]  R. Hall,et al.  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. , 1986, Nucleic acids research.

[105]  A. P. Williams,et al.  The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. , 2013, The Lancet. Infectious diseases.

[106]  A. Pühler,et al.  Occurrence of integron-associated resistance gene cassettes located on antibiotic resistance plasmids isolated from a wastewater treatment plant. , 2003, FEMS microbiology ecology.

[107]  P. Courvalin,et al.  Screening and Quantification of the Expression of Antibiotic Resistance Genes in Acinetobacter baumannii with a Microarray , 2009, Antimicrobial Agents and Chemotherapy.

[108]  F. Baquero,et al.  Antibiotics and antibiotic resistance in water environments. , 2008, Current opinion in biotechnology.

[109]  S. Hardwick,et al.  Gene cassettes encoding resistance to quaternary ammonium compounds: a role in the origin of clinical class 1 integrons? , 2009, The ISME Journal.

[110]  A. Boxall,et al.  Prevalence of Sulfonamide Resistance Genes in Bacterial Isolates from Manured Agricultural Soils and Pig Slurry in the United Kingdom , 2009, Antimicrobial Agents and Chemotherapy.

[111]  M. Gillings,et al.  Are humans increasing bacterial evolvability? , 2012, Trends in ecology & evolution.

[112]  D. Mazel,et al.  The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[113]  F. Baquero Environmental stress and evolvability in microbial systems. , 2009, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[114]  D. Mazel,et al.  Comparative analysis of superintegrons: engineering extensive genetic diversity in the Vibrionaceae. , 2003, Genome research.

[115]  R. Mackie,et al.  Environmental and Public Health Implications of Water Reuse: Antibiotics, Antibiotic Resistant Bacteria, and Antibiotic Resistance Genes , 2013, Antibiotics.

[116]  Yan Boucher,et al.  ACID: annotation of cassette and integron data , 2009, BMC Bioinformatics.

[117]  Didier Mazel,et al.  Structural basis for broad DNA-specificity in integron recombination , 2006, Nature.

[118]  J. Verhoef,et al.  Class I integrons in Gram-negative isolates from different European hospitals and association with decreased susceptibility to multiple antibiotic compounds. , 1998, The Journal of antimicrobial chemotherapy.

[119]  E. Denamur,et al.  Effect of human vicinity on antimicrobial resistance and integrons in animal faecal Escherichia coli. , 2006, The Journal of antimicrobial chemotherapy.

[120]  P. Naaber,et al.  The occurrence of antimicrobial resistance and class 1 integrons among commensal Escherichia coli isolates from infants and elderly persons , 2009, Annals of Clinical Microbiology and Antimicrobials.

[121]  L. Vinué,et al.  Change of integrons over time in Escherichia coli isolates recovered from healthy pigs and chickens. , 2013, Veterinary microbiology.

[122]  Reconstruction of an Active Integron Recombination Site after Integration of a Gene Cassette at a Secondary Site , 1999, Antimicrobial Agents and Chemotherapy.

[123]  T. Takeda,et al.  The Gene Encoding the Heat‐Stable Enterotoxin of Vibrio cholerae Is Flanked by 123‐Base Pair Direct Repeats , 1993, Microbiology and immunology.

[124]  K. Nielsen,et al.  Identical Miniature Inverted Repeat Transposable Elements Flank Class 1 Integrons in Clinical Isolates of Acinetobacter spp , 2013, Journal of Clinical Microbiology.

[125]  P. Ebner,et al.  Class 1 integrons in various Salmonella enterica serovars isolated from animals and identification of genomic island SGI 1 in Salmonella enterica var . , 2004 .

[126]  S. Yamasaki,et al.  Development of simple and rapid PCR‐fingerprinting methods for Vibrio cholerae on the basis of genetic diversity of the superintegron , 2009, Journal of applied microbiology.

[127]  Charles W. Knapp,et al.  Antibiotic Resistance Gene Abundances Associated with Waste Discharges to the Almendares River near Havana, Cuba , 2010, Environmental science & technology.

[128]  R. Hall,et al.  Plasmid evolution by acquisition of mobile gene cassettes: plasmid pIE723 contains the aadB gene cassette precisely inserted at a secondary site in the IncQ plasmid RSF1010 , 1995, Molecular microbiology.

[129]  T. Berendonk,et al.  Origin and Evolution of Antibiotic Resistance: The Common Mechanisms of Emergence and Spread in Water Bodies , 2011, Front. Microbio..

[130]  R M Hall,et al.  Characterisation of specific and secondary recombination sites recognised by the integron DNA integrase. , 1994, Nucleic acids research.

[131]  H. Jacquier,et al.  Translation regulation of integrons gene cassette expression by the attC sites , 2009, Molecular microbiology.

[132]  M. Scortichini,et al.  ASSESSMENT OF INTEGRON GENE CASSETTE ARRAYS IN STRAINS OF XANTHOMONAS FRAGARIAE AND X. ARBORICOLA pvs. FRAGARIAE AND PRUNI , 2006 .

[133]  D. Rowe-Magnus Integrase-directed recovery of functional genes from genomic libraries , 2009, Nucleic acids research.

[134]  J. Maurer,et al.  Incidence of Class 1 and 2 Integrases in Clinical and Commensal Bacteria from Livestock, Companion Animals, and Exotics , 2001, Antimicrobial Agents and Chemotherapy.

[135]  D. Mazel,et al.  Chromosomal toxin–antitoxin loci can diminish large‐scale genome reductions in the absence of selection , 2007, Molecular microbiology.

[136]  Tong Zhang,et al.  Characterization and quantification of class 1 integrons and associated gene cassettes in sewage treatment plants , 2009, Applied Microbiology and Biotechnology.

[137]  R M Hall,et al.  Site‐specific insertion of genes into integrons: role of the 59‐base element and determination of the recombination cross‐over point , 1991, Molecular microbiology.

[138]  Functional Characterization of a Cassette-Specific Promoter in the Class 1 Integron-Associated qnrVC1 Gene , 2012, Antimicrobial Agents and Chemotherapy.

[139]  P. H. Roy,et al.  IntI2 Integron Integrase in Tn7 , 2002, Journal of bacteriology.

[140]  Y. Arakawa,et al.  A novel integron-like element carrying the metallo-beta-lactamase gene blaIMP , 1995, Antimicrobial agents and chemotherapy.

[141]  Dong Li,et al.  Antibiotic Resistance Characteristics of Environmental Bacteria from an Oxytetracycline Production Wastewater Treatment Plant and the Receiving River , 2010, Applied and Environmental Microbiology.

[142]  A. McBain,et al.  Potential Impact of Increased Use of Biocides in Consumer Products on Prevalence of Antibiotic Resistance , 2003, Clinical Microbiology Reviews.

[143]  S. Djordjevic,et al.  Mobile elements, zoonotic pathogens and commensal bacteria: conduits for the delivery of resistance genes into humans, production animals and soil microbiota , 2013, Front. Microbiol..

[144]  R. Hall,et al.  A novel family of potentially mobile DNA elements encoding site‐specific gene‐integration functions: integrons , 1989, Molecular microbiology.

[145]  Rui Wu,et al.  Analysis of antimicrobial resistance and class 1 integrons among strains from upper respiratory tract of healthy adults. , 2013, Journal of thoracic disease.

[146]  P. H. Roy,et al.  Transposon Tn5090 of plasmid R751, which carries an integron, is related to Tn7, Mu, and the retroelements , 1994, Journal of bacteriology.

[147]  M. Labbate,et al.  Deletion of Integron-Associated Gene Cassettes Impact on the Surface Properties of Vibrio rotiferianus DAT722 , 2013, PloS one.

[148]  R. Hall,et al.  Integrons or super integrons? , 2004, Microbiology.

[149]  P. H. Roy,et al.  Diversity and relative strength of tandem promoters for the antibiotic-resistance genes of several integrons. , 1994, Gene.

[150]  M. Gillings,et al.  Mobilization of a Tn402-Like Class 1 Integron with a Novel Cassette Array via Flanking Miniature Inverted-Repeat Transposable Element-Like Structures , 2009, Applied and Environmental Microbiology.

[151]  H. Stokes,et al.  Novel integrons and gene cassettes from a Cascadian submarine gas-hydrate-bearing core. , 2014, FEMS microbiology ecology.

[152]  E. Topp,et al.  Management Options for Reducing the Release of Antibiotics and Antibiotic Resistance Genes to the Environment , 2013, Environmental health perspectives.

[153]  W. Doolittle,et al.  Coral-mucus-associated Vibrio integrons in the Great Barrier Reef: genomic hotspots for environmental adaptation , 2011, The ISME Journal.

[154]  Didier Mazel,et al.  Integrons: agents of bacterial evolution , 2006, Nature Reviews Microbiology.

[155]  K. Konstantinidis,et al.  Long-term exposure to benzalkonium chloride disinfectants results in change of microbial community structure and increased antimicrobial resistance. , 2013, Environmental science & technology.

[156]  P. H. Roy,et al.  What are superintegrons? , 2007, Nature Reviews Microbiology.

[157]  P. Ebner,et al.  Class 1 integrons in various Salmonella enterica serovars isolated from animals and identification of genomic island SGI1 in Salmonella enterica var. Meleagridis. , 2004, The Journal of antimicrobial chemotherapy.

[158]  E. Krin,et al.  Connecting Environment and Genome Plasticity in the Characterization of Transformation-Induced SOS Regulation and Carbon Catabolite Control of the Vibrio cholerae Integron Integrase , 2012, Journal of bacteriology.

[159]  C. Manaia,et al.  Antibiotic resistance in waste water and surface water and human health implications , 2011 .

[160]  J. E. Peters,et al.  Tn7: smarter than we thought , 2001, Nature Reviews Molecular Cell Biology.

[161]  S. Minakhina,et al.  Tn5053 family transposons are res site hunters sensing plasmidal res sites occupied by cognate resolvases , 1999, Molecular microbiology.

[162]  D. Mazel,et al.  Erythromycin Esterase Gene ere(A) Is Located in a Functional Gene Cassette in an Unusual Class 2 Integron , 2003, Antimicrobial Agents and Chemotherapy.

[163]  I. Droppo,et al.  Diversity of Integron- and Culture-Associated Antibiotic Resistance Genes in Freshwater Floc , 2012, Applied and Environmental Microbiology.

[164]  G. Cambray,et al.  The SOS Response Controls Integron Recombination , 2009, Science.

[165]  D. Mevius,et al.  Occurrence and characteristics of class 1, 2 and 3 integrons in Escherichia coli, Salmonella and Campylobacter spp. in the Netherlands. , 2007, The Journal of antimicrobial chemotherapy.

[166]  M. Casellas,et al.  An antibiotic-resistant class 3 integron in an Enterobacter cloacae isolate from hospital effluent. , 2013, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[167]  C. Johansson,et al.  Integron integrase binds to bulged hairpin DNA. , 2004, Nucleic acids research.

[168]  Andrew B. Mahon,et al.  Recombination Activity of a Distinctive Integron-Gene Cassette System Associated with Pseudomonas stutzeri Populations in Soil , 2003, Journal of bacteriology.

[169]  R. Hall,et al.  The integrons In0, In2, and In5 are defective transposon derivatives , 1996, Journal of bacteriology.

[170]  K. Schlacher,et al.  Lessons from 50 years of SOS DNA-damage-induced mutagenesis , 2007, Nature Reviews Molecular Cell Biology.

[171]  J. Sofos,et al.  Characterization and transferability of class 1 integrons in commensal bacteria isolated from farm and nonfarm environments. , 2010, Foodborne pathogens and disease.

[172]  P. H. Roy,et al.  Site-specific insertion of three structural gene cassettes in transposon Tn7 , 1991, Journal of bacteriology.

[173]  S. Mindlin,et al.  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 , 1995, Molecular microbiology.

[174]  M. Waldor,et al.  The Three Vibrio cholerae Chromosome II-Encoded ParE Toxins Degrade Chromosome I following Loss of Chromosome II , 2010, Journal of bacteriology.

[175]  S. Salzberg,et al.  DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae , 2000, Nature.

[176]  Y. Boucher,et al.  Integron Gene Cassettes: A Repository of Novel Protein Folds with Distinct Interaction Sites , 2013, PloS one.

[177]  A. Buschmann,et al.  Antimicrobial use in aquaculture re-examined: its relevance to antimicrobial resistance and to animal and human health. , 2013, Environmental microbiology.

[178]  G. Cornaglia,et al.  Clonal Relatedness and Conserved Integron Structures in Epidemiologically Unrelated Pseudomonas aeruginosa Strains Producing the VIM-1 Metallo-β-Lactamase from Different Italian Hospitals , 2005, Antimicrobial Agents and Chemotherapy.

[179]  Didier Mazel,et al.  Integron cassette insertion: a recombination process involving a folded single strand substrate , 2005, The EMBO journal.

[180]  A. Holmes,et al.  An unusual integron in Treponema denticola. , 2004, Microbiology.

[181]  E. Coiera,et al.  Gene cassettes and cassette arrays in mobile resistance integrons. , 2009, FEMS microbiology reviews.

[182]  C. Quiroga,et al.  Novel Rearrangement of a Class 2 Integron in Two Non-Epidemiologically Related Isolates of Acinetobacter baumannii , 2005, Antimicrobial Agents and Chemotherapy.

[183]  M. Pons,et al.  Dynamic assessment of the floc morphology, bacterial diversity, and integron content of an activated sludge reactor processing hospital effluent. , 2013, Environmental science & technology.

[184]  H. Heuer,et al.  Diverse aadA gene cassettes on class 1 integrons introduced into soil via spread manure. , 2009, Research in microbiology.

[185]  J. H. Crosa,et al.  Identification and cloning of a tetracycline resistance gene from the fish pathogen Vibrio salmonicida , 1992, Antimicrobial Agents and Chemotherapy.

[186]  D. Skurnik,et al.  Occurrence of antibiotic resistance and class 1, 2 and 3 integrons in Escherichia coli isolated from a densely populated estuary (Seine, France). , 2009, FEMS microbiology ecology.

[187]  Jeremy L. Pinyon,et al.  Commensal Escherichia coli of healthy humans: a reservoir for antibiotic-resistance determinants. , 2010, Journal of medical microbiology.

[188]  J. Blázquez,et al.  Side effects of antibiotics on genetic variability. , 2009, FEMS microbiology reviews.

[189]  John W. Beaber,et al.  SOS response promotes horizontal dissemination of antibiotic resistance genes , 2004, Nature.

[190]  B. Olsen,et al.  Dissemination of Multidrug-Resistant Bacteria into the Arctic , 2008, Emerging infectious diseases.

[191]  M. Labbate,et al.  Gene cassette transcription in a large integron-associated array , 2010, BMC Genetics.

[192]  S. Mendo,et al.  Molecular Characterization of a New Class 3 Integron in Klebsiella pneumoniae , 2003, Antimicrobial Agents and Chemotherapy.

[193]  J. Mullins,et al.  Photonic detection of bacterial pathogens in living hosts , 1995, Molecular microbiology.

[194]  J. Martínez Antibiotics and Antibiotic Resistance Genes in Natural Environments , 2008, Science.

[195]  Magali Casellas,et al.  Integron Involvement in Environmental Spread of Antibiotic Resistance , 2012, Front. Microbio..

[196]  N. Iqbal,et al.  Characterization of the phd-doc and ccd Toxin-Antitoxin Cassettes from Vibrio Superintegrons , 2013, Journal of bacteriology.

[197]  D. Barceló,et al.  Emerging Organic Contaminants and Human Health , 2012 .

[198]  S. Hardwick,et al.  Quantification of class 1 integron abundance in natural environments using real-time quantitative PCR. , 2008, FEMS microbiology letters.

[199]  P. Nordmann,et al.  Characterization of In53, a Class 1 Plasmid- and Composite Transposon-Located Integron of Escherichia coli Which Carries an Unusual Array of Gene Cassettes , 2001, Journal of bacteriology.

[200]  R M Hall,et al.  Site-specific deletion and rearrangement of integron insert genes catalyzed by the integron DNA integrase , 1992, Journal of bacteriology.

[201]  E. Wellington,et al.  Integron Prevalence and Diversity in Manured Soil , 2010, Applied and Environmental Microbiology.

[202]  Masahira Hattori,et al.  Genome sequence of Vibrio parahaemolyticus: a pathogenic mechanism distinct from that of V cholerae , 2003, The Lancet.

[203]  C. M. Collis,et al.  Efficiency of Recombination Reactions Catalyzed by Class 1 Integron Integrase IntI1 , 2001, Journal of bacteriology.

[204]  R. Norman,et al.  Abundance of class 1-3 integrons in South Carolina estuarine ecosystems under high and low levels of anthropogenic influence. , 2013, Marine pollution bulletin.

[205]  Yuzhen Ye,et al.  The gain and loss of chromosomal integron systems in the Treponema species , 2013, BMC Evolutionary Biology.

[206]  Min Qiao,et al.  Impact of reclaimed water irrigation on antibiotic resistance in public parks, Beijing, China. , 2014, Environmental pollution.

[207]  K. Nielsen,et al.  The blaIMP-5-carrying integron in a clinical Acinetobacter baumannii strain is flanked by miniature inverted-repeat transposable elements (MITEs). , 2011, The Journal of antimicrobial chemotherapy.

[208]  R. Stepanauskas,et al.  Influence of industrial contamination on mobile genetic elements: class 1 integron abundance and gene cassette structure in aquatic bacterial communities , 2008, The ISME Journal.

[209]  D. Mazel,et al.  Bacterial resistance evolution by recruitment of super‐integron gene cassettes , 2002, Molecular microbiology.

[210]  Michael R Gillings,et al.  Gene flow, mobile genetic elements and the recruitment of antibiotic resistance genes into Gram-negative pathogens. , 2011, FEMS microbiology reviews.

[211]  E. Kristiansson,et al.  Pyrosequencing of Antibiotic-Contaminated River Sediments Reveals High Levels of Resistance and Gene Transfer Elements , 2011, PloS one.

[212]  António Correia,et al.  INTEGRALL: a database and search engine for integrons, integrases and gene cassettes , 2009, Bioinform..

[213]  D. Mazel,et al.  A distinctive class of integron in the Vibrio cholerae genome. , 1998, Science.

[214]  F. Cabello,et al.  Heavy use of prophylactic antibiotics in aquaculture: a growing problem for human and animal health and for the environment. , 2006, Environmental microbiology.

[215]  K. Hansson,et al.  Non‐palindromic attI sites of integrons are capable of site‐specific recombination with one another and with secondary targets , 1997, Molecular microbiology.

[216]  Mina Rho,et al.  Oral Spirochetes Implicated in Dental Diseases Are Widespread in Normal Human Subjects and Carry Extremely Diverse Integron Gene Cassettes , 2012, Applied and Environmental Microbiology.

[217]  A. Summers,et al.  Intracellular steady-state concentration of integron recombination products varies with integrase level and growth phase. , 2009, Journal of molecular biology.

[218]  Blair S Nield,et al.  The gene cassette metagenome is a basic resource for bacterial genome evolution. , 2003, Environmental microbiology.

[219]  Michael R. Gillings,et al.  Evolutionary consequences of antibiotic use for the resistome, mobilome and microbial pangenome , 2013, Front. Microbio..

[220]  A. Barker,et al.  VlpA of Vibrio cholerae O1: the first bacterial member of the alpha 2-microglobulin lipocalin superfamily. , 1997, Microbiology.

[221]  W. Doolittle,et al.  Recovery and evolutionary analysis of complete integron gene cassette arrays from Vibrio , 2006, BMC Evolutionary Biology.

[222]  Yan Boucher,et al.  The Evolution of Class 1 Integrons and the Rise of Antibiotic Resistance , 2008, Journal of bacteriology.

[223]  D. Mazel,et al.  Shuffling of DNA cassettes in a synthetic integron. , 2013, Methods in molecular biology.

[224]  M. Scortichini,et al.  Integron variability in Xanthomonas arboricola pv. juglandis and Xanthomonas arboricola pv. pruni strains. , 2008, FEMS microbiology letters.

[225]  C. M. Collis,et al.  Gene cassettes from the insert region of integrons are excised as covalently closed circles , 1992, Molecular microbiology.

[226]  J. Martínez,et al.  Natural Antibiotic Resistance and Contamination by Antibiotic Resistance Determinants: The Two Ages in the Evolution of Resistance to Antimicrobials , 2012, Front. Microbio..

[227]  Y. Boucher,et al.  Class 1 Integrons Potentially Predating the Association with Tn402-Like Transposition Genes Are Present in a Sediment Microbial Community , 2006, Journal of bacteriology.

[228]  G. Cambray,et al.  Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons , 2011, Mobile DNA.

[229]  A. Boxall,et al.  A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment. , 2006, Chemosphere.

[230]  I. Paulsen,et al.  The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs , 1996, Molecular microbiology.

[231]  J. Tiedje,et al.  Worldwide Prevalence of Class 2 Integrases outside the Clinical Setting Is Associated with Human Impact , 2009, Applied and Environmental Microbiology.

[232]  Nancy Messier,et al.  Integron Integrases Possess a Unique Additional Domain Necessary for Activity , 2001, Journal of bacteriology.

[233]  R. Hall,et al.  Integrons found in different locations have identical 5' ends but variable 3' ends , 1994, Journal of bacteriology.

[234]  J. Posfai,et al.  Discovery and distribution of super‐integrons among Pseudomonads , 2001, Molecular microbiology.

[235]  Ola Sköld,et al.  Sulfonamide resistance: mechanisms and trends. , 2000, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[236]  M. Gillings,et al.  New enzymes from environmental cassette arrays: Functional attributes of a phosphotransferase and an RNA‐methyltransferase , 2004, Protein science : a publication of the Protein Society.

[237]  Structural Features of Single-Stranded Integron Cassette attC Sites and Their Role in Strand Selection , 2009, PLoS genetics.

[238]  P. Johnsen,et al.  Costly Class-1 integrons and the domestication of the the functional integrase , 2013, Mobile genetic elements.

[239]  R M Hall,et al.  Definition of the attI1 site of class 1 integrons. , 2000, Microbiology.

[240]  Quok-Cheong Choo,et al.  New integron gene arrays from multiresistant clinical isolates of members of the Enterobacteriaceae and Pseudomonas aeruginosa from hospitals in Malaysia. , 2013, Journal of medical microbiology.

[241]  M. Cassini,et al.  Class 1 Integrons in Environments with Different Degrees of Urbanization , 2012, PloS one.

[242]  P. Nordmann,et al.  Integron Mobilization Unit as a Source of Mobility of Antibiotic Resistance Genes , 2008, Antimicrobial Agents and Chemotherapy.

[243]  H. A. Saka,et al.  CARB-9, a Carbenicillinase Encoded in the VCR Region of Vibrio cholerae Non-O1, Non-O139 Belongs to a Family of Cassette-Encoded β-Lactamases , 2004, Antimicrobial Agents and Chemotherapy.

[244]  M. Gillings,et al.  Into the Wild: Dissemination of Antibiotic Resistance Determinants via a Species Recovery Program , 2013, PloS one.

[245]  Andrew P. Martin,et al.  Insights and inferences about integron evolution from genomic data , 2008, BMC Genomics.

[246]  Célia M. Manaia,et al.  Human health implications of clinically relevant bacteria in wastewater habitats , 2013, Environmental Science and Pollution Research.

[247]  M. Gillings,et al.  Mobile Gene Cassettes: A Fundamental Resource for Bacterial Evolution , 2004, The American Naturalist.

[248]  A. Mandal,et al.  Diverse Gene Cassettes in Class 1 Integrons of Facultative Oligotrophic Bacteria of River Mahananda, West Bengal, India , 2013, PloS one.

[249]  R. Hall Integrons and gene cassettes: hotspots of diversity in bacterial genomes , 2012, Annals of the New York Academy of Sciences.

[250]  P. White,et al.  Integrons and Gene Cassettes in theEnterobacteriaceae , 2001, Antimicrobial Agents and Chemotherapy.

[251]  R M Hall,et al.  Expression of antibiotic resistance genes in the integrated cassettes of integrons , 1995, Antimicrobial agents and chemotherapy.

[252]  W. F. Fricke,et al.  Natural Transformation Facilitates Transfer of Transposons, Integrons and Gene Cassettes between Bacterial Species , 2012, PLoS pathogens.

[253]  Y. Arakawa,et al.  PCR Typing of Genetic Determinants for Metallo-β-Lactamases and Integrases Carried by Gram-Negative Bacteria Isolated in Japan, with Focus on the Class 3 Integron , 2003, Journal of Clinical Microbiology.

[254]  R. Xia,et al.  Molecular diversity of class 2 integrons in antibiotic-resistant gram-negative bacteria found in wastewater environments in China , 2013, Ecotoxicology.

[255]  Tong Zhang,et al.  Plasmid Metagenome Reveals High Levels of Antibiotic Resistance Genes and Mobile Genetic Elements in Activated Sludge , 2011, PloS one.