Integrons are genetic elements that acquire and exchange exogenous DNA, known as gene cassettes, by a site-specific recombination 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 determinant. The affiliation of multiresistant integrons (MRIs), which contain various combinations of antibiotic resistance gene cassettes, 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 MRI integrase, IntI1. We have also identified equivalent integron superstructures in nine distinct genera throughout the ␥-proteobacterial radiation. Phylogenetic analysis revealed that the evolutionary 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 identical 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 genecapture system for bacterial innovation. T he impact of lateral gene transfer on bacterial evolution is underscored by the realization that foreign DNA can represent up to one-fifth of a given bacterial genome (1). Perhaps the most striking embodiment of its affect on microbial adaptation has been the rapid and widespread emergence of similar antibiotic-resistance profiles among phylogenetically diverse Gram-negative clinical and environmental isolates over the last half-century (2). The localization of antibiotic-resistance determinants to mobile entities such as plasmids and transposons readily explained this phenomenon (3-6). Closer examination revealed that in many cases a new type of genetic element, termed an integron, harbored the resistance determinants. Integrons are natural cloning and expression systems that incorporate open reading frames and convert them to functional genes (for review see refs. 7 and 8). The integron platform codes for an integrase (intI) that mediates recombination between a proximal primary recombination site (attI) and a secondary target called an attC site [or 59-base element (59be)]. The attC site is normally found associated with a single open reading frame (ORF), and the attC-ORF ...
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