The evolutionary history of chromosomal super-integrons provides an ancestry for multiresistant integrons

摘要

Integrons are genetic elements that acquire and exchange exog- enous DNA, known as gene cassettes, by a site-specific recombi- nation mechanism. Characterized gene cassettes consist of a target recombination sequence (attC site) usually associated with a single open reading frame coding for an antibiotic resistance determi- nant. The affiliation of multiresistant integrons (MRIs), which contain various combinations of antibiotic resistance gene cas- settes, with transferable elements underlies the rapid evolution of multidrug resistance among diverse Gram-negative bacteria. Yet the origin of MRIs remains unknown. Recently. a chromosomal super-integron (SI) harboring hundreds of cassettes was identified in the Vibrio cholerae genome. Here. we demonstrate that the activity of its associated integrase is identical to that of the MRl integrase, Intl1. We have also identified equivalent integron su- perstructures in nine distinct genera throughout the γ-proteobac- terial radiation. Phylogenetic analysis reveaIed that the evolution- ary history of the system paralleled that of the radiation, indicating that integrons are ancient structures. The attC sites of the 63 antibiotic-resistance gene cassettes identified thus far in MRIs are highly variable. Strikingly. one-fifth of these were virtually iden- ticaI to the highly related yet species-specific attC sites of the SIs described here. Furthermore. antimicrobial resistance homologues were identified among the thousands of genes entrapped by these SIs. Because the gene cassettes of SIs are substrates for MRIs, these data identify SIs as the source of contemporary MRIs and their cassettes. However, our demonstration of the metabolic functions, beyond antibiotic resistance and virulence, of three distinct SI gene cassettes indicates that integrons function as a general gene- capture system for bacterial innovation.