Rowe-Magnus D A, Guerout A M, Ploncard P, Dychinco B, Davies J, Mazel D
Unité de Programmation Moléculaire et Toxicologie Génétique, Centre National de la Recherche Scientifique Unité de Recherche Associée 1444, Département des Biotechnologies, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris, France.
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):652-7. doi: 10.1073/pnas.98.2.652.
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 gamma-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 gene-capture system for bacterial innovation.
整合子是通过位点特异性重组机制获取并交换外源DNA（即基因盒）的遗传元件。特征性基因盒由一个靶重组序列（attC位点）组成，该序列通常与一个编码抗生素抗性决定簇的单一开放阅读框相关联。含有多种抗生素抗性基因盒组合的多抗性整合子（MRI）与可转移元件的关联是不同革兰氏阴性菌中多药耐药性快速演变的基础。然而，MRI的起源仍然未知。最近，在霍乱弧菌基因组中鉴定出一个含有数百个基因盒的染色体超级整合子（SI）。在这里，我们证明其相关整合酶的活性与MRI整合酶IntI1的活性相同。我们还在整个γ-变形菌纲辐射范围内的九个不同属中鉴定出了等效的整合子超结构。系统发育分析表明，该系统的进化历史与辐射的进化历史平行，这表明整合子是古老的结构。迄今为止在MRI中鉴定出嘅63个抗生素抗性基因盒的attC位点高度可变。令人惊讶的是，其中五分之一与这里描述的SI的高度相关但物种特异性的attC位点几乎相同。此外，在这些SI捕获的数千个基因中鉴定出了抗菌抗性同源物。由于SI的基因盒是MRI的底物，这些数据将SI确定为当代MRI及其基因盒的来源。然而，我们对三个不同的SI基因盒的代谢功能（除抗生素抗性和毒力之外）的证明表明，整合子作为细菌创新的通用基因捕获系统发挥作用。
