IS and the IS family: versatile resistance gene movers and genome reorganizers.

In Gram-negative bacteria, the insertion sequence IS is highly active in disseminating antibiotic resistance genes. IS can recruit a gene or group of genes into the mobile gene pool and support their continued dissemination to new locations by creating pseudo-compound transposons (PCTs) that can be further mobilized by the insertion sequence (IS). IS can also enhance expression of adjacent potential resistance genes. IS encodes a DDE transposase but has unique properties. It forms cointegrates between two separate DNA molecules using two mechanisms. The well-known copy-in (replicative) route generates an additional IS copy and duplicates the target site. The recently discovered and more efficient and targeted conservative mechanism requires an IS in both participating molecules and does not generate any new sequence. The unit of movement for PCTs, known as a translocatable unit or TU, includes only one IS. TU formed by homologous recombination between the bounding ISs can be reincorporated via either cointegration route. However, the targeted conservative reaction is key to generation of arrays of overlapping PCTs seen in resistant pathogens. Using the copy-in route, IS can also act on a site in the same DNA molecule, either inverting adjacent DNA or generating an adjacent deletion plus a circular molecule carrying the DNA segment lost and an IS copy. If reincorporated, these circular molecules create a new PCT. IS is the best characterized IS in the IS family, which includes IS/IS, ISSau10, IS, IS, and IS that are also implicated in spreading resistance genes in Gram-positive and Gram-negative pathogens.