Chapter 14 : Evolution of Integrons and Evolution of Antibiotic Resistance

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Integrons were only formally identified as agents of antibiotic resistance gene recruitment in the late 1980s following the observation that transposons and R-plasmids expressing different antibiotic resistance phenotypes shared the same genetic backbone and differed only in the resistance genes they harbored. Integrons can be divided into two distinct subsets, the mobile integrons (MIs), linked to mobile DNA elements and primarily involved in the spread of antibiotic-resistance genes, and the superintegrons (SIs). Integrons are undoubtedly ancient entities, as indicated by the species-specific clustering of the respective SI integrase genes in a pattern that adheres, in several cases, to the line of descent among the bacterial species in which they are located. Thus, the establishment of SIs likely predates speciation within the respective genera, indicating that integrons are ancient structures that have been impacting on the evolution of bacterial genomes for hundreds of millions of years. The determination of the diverse number of metabolic activities associated with SI cassettes (other than antibiotic resistance and virulence) indicates that integrons operate as a general gene capture system in bacterial adaptation. Integrases encoded by integrons mediate recombination involving two types of sites-their specific attI site and the cassette-associated attC site-and are able to recombine distantly related DNA sequences. With the discovery of SIs, and of the thousands of gene cassettes associated with integrons that are located in the genomes of environmental bacterial species, the importance of these elements clearly extends beyond the phenomenon of antibiotic resistance.

Citation: Mazel D. 2008. Evolution of Integrons and Evolution of Antibiotic Resistance, p 160-154. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch14
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Image of Figure 1.
Figure 1.

Structural comparison of a “classical” mobile integron and the V. cholerae N16961 SI. (Top) Schematic representation of In40; the various resistance genes are associated with different attC sites (see text). Antibiotic-resistance cassettes confer resistance to the following compounds: aacA4, aminoglycosides; qac, quarternary ammonium compounds; cmlA2, chloramphenicol; oxa9, beta-lactams. The sul gene, which provides resistance to sulfonamides, is not a gene cassette. (Bottom) The open reading frames are separated by highly homologous sequences, the VCRs. See text for details.

Citation: Mazel D. 2008. Evolution of Integrons and Evolution of Antibiotic Resistance, p 160-154. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch14
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Image of Figure 2.
Figure 2.

Phylogenetic relationship of the integron intI genes among the proteobacteria. Dendrogram based on known intI gene sequences. The tree was rooted using XerC and XerD from E. coli (Eco) and Thiobacillus denitrificans ATCC 25259 (Thd). The integrases from the five classes of MI are boxed (accession numbers for intIHS and intI9_SXT are AJ277063 and AY035340, respectively). Abbreviations for the organism in which the integron integrases are found is as follows: Azoarcus sp. EbN1 (Azo), Dechloromonas aromatica (Daro), Escherichia coli (Eco), Geobacter metallireducens (Gme), Listonella pelagia (Lpe), Listonella anguilarum (Lan), Methylobacillus flagellatus (Meflag), Nitrococcus mobilis (Nmo), Nitrosomonas europaea (Neu), Photobacterium profudum (Ppr), Pseudomonas alcaligenes (Palc), Pseudomonas mendocina (Pme), Pseudomonas stutzeri BAM (PstuBAM), P. stutzeri Q (PstuQ), Reinekea sp. (Rei), Rhodopirellula baltica (Rhbal), Rubrivivax gelatinosus (Ruge), Saccharophagus degradans (Sadeg), Shewanella amazonensis (Sam), Shewanella oneidensis (Son), Shewanella putrefaciens (Spu), Shewanella sp. MR-7 (Smr7), Thiobacillus denitrificans (Thd), Treponema denticola (Tde), Vibrio cholerae (Vch), Vibrio fischeri (Vfi), Vibrio metschnikovii (Vme), Vibrio mimicus (Vmi), Vibrio parahaemolyticus (Vpa), Vibrio splendidus (Vsp), Xanthomonas campestris (Xca), Xanthomonas oryzae (Xor), and Xanthomonas species (Xsp). The sources of IntI6, IntI7, and IntI8 are unknown. The tree displayed is the best distance neighbor-joining tree obtained using MEGA3. Bootstrap support values represent the consensus of distance neighbor-joining trees obtained from 1,000 pseudo-replicates of the dataset. Branch lengths were drawn proportional to the amount of evolution based on genetic distances. Accession numbers (when available) can be found in Table 1.

Citation: Mazel D. 2008. Evolution of Integrons and Evolution of Antibiotic Resistance, p 160-154. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch14
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Image of Figure 3.
Figure 3.

Integron recombination sites. (A) Sequence of the double stranded attCaadA7 site. (B) Proposed secondary structure for the attCaadA7 bottom strand (bs). The inverted repeats L, L′ and L″, R, R′ and R″ are indicated with black arrows, and the asterisk (*) shows the position of the protruding G present in L″ relative to L′. The putative IntI1 binding domains as defined by Stokes et al. (1997) are marked with grey boxes. Vertical arrows indicate crossover position. The secondary structure was determined using the MFOLD (Walter et al., 1994) online interface at the Pasteur Institute.

Citation: Mazel D. 2008. Evolution of Integrons and Evolution of Antibiotic Resistance, p 160-154. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch14
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Table 1.

Bacterial species harboring chromosomal integrons and superintegrons

Citation: Mazel D. 2008. Evolution of Integrons and Evolution of Antibiotic Resistance, p 160-154. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch14

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