Integrons are powerful recombination systems found in bacteria, which act as platforms capable of capturing, stockpiling, excising and reordering mobile elements called cassettes. These dynamic genetic machineries confer a very high potential of adaptation to their host and have quickly found themselves at the forefront of antibiotic resistance, allowing for the quick emergence of multi-resistant phenotypes in a wide range of bacterial species. Part of the success of the integron is explained by its ability to integrate various environmental and biological signals in order to allow the host to respond to these optimally. In this review, we highlight the substantial interconnectivity that exists between integrons and their hosts and its importance to face changing environments. We list the factors influencing the expression of the cassettes, the expression of the integrase, and the various recombination reactions catalyzed by the integrase. The combination of all these host factors allows for a very tight regulation of the system at the cost of a limited ability to spread by horizontal gene transfer and function in remotely related hosts. Hence, we underline the important consequences these factors have on the evolution of integrons. Indeed, we propose that sedentary chromosomal integrons that were less connected or connected via more universal factors are those that have been more successful upon mobilization in mobile genetic structures, in contrast to those that were connected to species-specific host factors. Thus, the level of specificity of the involved host factors network may have been decisive for the transition from chromosomal integrons to the mobile integrons, which are now widespread. As such, integrons represent a perfect example of the conflicting relationship between the ability to control a biological system and its potential for transferability.

The integron is a bacterial recombination system that allows acquisition, stockpiling and expression of promoterless genes embedded in cassettes. Some integrons, like the one found in the second chromosome of Vibrio cholerae, can be particularly massive and contain hundreds of non-expressed cassettes. It is unclear how such genetic structures can be stabilized in bacterial genomes. Here, we reveal that the orientation of integrons toward replication within bacterial chromosomes is essential to their stability. Indeed, we show that upon inversion of the V. cholerae chromosomal integron, its plasticity is dramatically increased. This correlates with a strong growth defect which we show is mostly due to the excision of a particular type of cassettes bearing their own promoter and encoding toxin-antitoxin systems. This so called abortive excision of toxin-antitoxin systems can prevent the inversion of chromosomal integrons and the associated extensive loss of cassettes. Our analysis of the available sedentary chromosomal integrons in genome database show a robust correlation between the size of the cassette array and the number of toxin-antitoxin cassettes. This study thus provides a striking example of the relationship between genome organization, genome stability, and an emerging property of toxin-antitoxin systems.

Integrons are genetic elements found exclusively in bacteria. They are well known for their role in disseminating antibiotic resistance genes among pathogens and more generally for enabling bacteria to rapidly adapt to changing environmental conditions. Integrons constitute a natural system to capture, stockpile, shuffle, express and disseminate genes embedded in cassettes. All these events are governed by the integron integrase through site-specific recombination between integron att sites (attC and attI sites). Here, we demonstrate that integron integrase can efficiently catalyze the insertion of cassettes in bacterial genomes, outside the att sites carried by the integron system. Surprisingly, analysis of more than 500,000 independent clones revealed that the genome recombination sites differ greatly, in terms of sequence and structure, from both classical attC and attI recombination sites. We named these new sites attG. Notably, among these a few are driving integration at very high rates. We also showed that, once inserted in genomes, cassettes can be expressed if located near a bacterial promoter. Moreover, even if occurring at low frequency, genome inserted cassettes can be excised precisely or imprecisely, inducing in this latter case, chromosomal modifications. These results unveil a new route for antibiotic resistance dissemination and expand the role of integrons in bacterial genome evolution.