Integron: What Does it Contain and What Does it Do?

Keywords

Mobile genetic elements, class 1 integron, horizontal or lateral gene transfer, homologous recombination, transposition, transformation, conjugation, transduction, antibiotic resistance.

Introduction

Integrons are genetic elements able to acquire and rearrange open reading frames (ORFs) embedded in gene cassette units and convert them to functional genes by ensuring their correct expression. They are widely known for their role in the dissemination of antibiotic resistance, particularly among gram-negative bacterial pathogens.

Their role has been broadened with the discovery of chromosomal integron (CI) structures in the genomes of hundreds of bacterial species. Integrons are chromosomal elements, and their mobilization onto plasmids has been fostered by transposons and selected by the intensive use of antibiotics.

Integrons occur in all environments, can move between species and lineages over evolutionary time frames and have access to a vast pool of novel genes whose functions are largely yet to be determined.

Over the last decade, exploration of integron diversity in natural environments has shown that they are more than just a curious feature of antibiotic-resistant pathogens but have a more general and important role in bacterial adaptation and genome evolution.

Occurrence

Integrons may be found as part of mobile genetic elements such as plasmids and transposons. Integrons can also be found in chromosomes.

Terminology

Integrons term has been used for various cassette array lengths or for integrons on bacterial chromosomes (plasmids). An integron located on a bacterial chromosome is termed a sedentary chromosomal integron, and one associated with transposons or plasmids is called a mobile integron.

Structure of Integrons

All integrons share three essential core features, whose combined activities capture and subsequently express exogenous genes as part of gene cassettes.

• a gene encoding for a site-specific recombinase: intI, belonging to the integrase family.
• a proximal recombination site: attI, which is recognized by the integrase and at which gene cassettes may be inserted.
• a promoter: Pc, which directs transcription of cassette-encoded genes.

Gene cassettes

An integron will usually contain one or more gene cassettes that have been incorporated into it. The gene cassettes may encode genes for antibiotic resistance, although most genes in integrons are uncharacterized. An attC sequence is a repeat that flanks cassettes and enables cassettes to be integrated at the attI site, excised, and undergo horizontal gene transfer.

Function

Cassette maintenance requires that they be integrated within a replicative element (chromosome, plasmids). The integrase encoded by the integron preferentially catalyzes two types of recombination reaction:

• attC x attC, which results in cassette excision.
• attI x attC, which allows integration of the cassette at the attI site of the integron.

Once inserted, the cassette is maintained during cell division. Successive integrations of gene cassettes result in the formation of a series of cassettes. The cassette integrated last is then the one closest to the Pc promoter at the attI site. The IntI-catalyzed mode of recombination involves structured single-stranded DNA and gives the attC site recognition mode unique characteristics.

The integration of gene cassettes within an integron also provides a Pc promoter that allows expression of all cassettes in the array, much like an operon. The level of gene expression of a cassette is then a function of the number and nature of the cassettes that precede it.

In 2009, Didier Mazel and his team showed that the expression of the IntI integrase was controlled by the bacterial SOS response, thus coupling this adaptive apparatus to the stress response in bacteria.

Integrons in the Present: The Rise of Antibiotic Resistance

Integrons are major players in the spread of antibiotic resistance, particularly in Gram-negative pathogens. There are five classes of “mobile” integrons, all associated with antibiotic resistance: classes 1, 2, and 3, usually recovered from clinical contexts; class 4, found on the SXT element of Vibrio cholerae; and class 5, found on the pRSV1 plasmid of Alivibrio salmonicida.

• Origin of class 1 integrons as vectors for antibiotic resistance
• Origin of class 2 clinical integrons
• Origin of class 3 clinical integrons

Integrons in the Future

DNA elements have made their way into diverse bacterial hosts, both commensals and pathogens, which have, in turn, colonized humans, their companion animals, and them domesticates.

The result is that integrons, their antibiotic resistance genes, and the mobile DNA elements they reside upon have become widely distributed, highly diverse, and abundant in human-dominated ecosystems. Integrons are exquisitely positioned to sample and express potentially any gene in the biosphere and to do so without perturbing existing genes. Consequently, they have the power to promote adaptation to changing environmental conditions by rapidly generating genetic variation.

This allows integron-containing cells to overcome human strategies for controlling bacterial growth, but it also offers rich opportunities for gene prospecting and construction of new biosynthetic pathways.

Conclusion

Integrons are remarkable genetic platforms with the ability to acquire, rearrange, and express diverse genes sampled from the microbial pangenome. Integrons are far more than a curious phenomenon of clinical concern.

They are an ancient, diverse, and widespread mechanism for generating genomic novelty and triggering adaptive responses in bacteria. It provides a powerful platform for biotechnology, where potentially any gene could be accessed, manipulated, and expressed using integron activity.

It would also improve the potential of using integrons as platforms for synthetic biology. There is potential for better health outcomes, better environmental management, and better understanding of the broad sweep of microbial evolution.