How Do Transposable Elements Activate Expression of Transcriptionally Silent Antibiotic Resistance Genes?

Abstract

The rapidly emerging phenomenon of antibiotic resistance threatens to substantially reduce the efficacy of available antibacterial therapies. Dissemination of resistance, even between phylogenetically distant bacterial species, is mediated mainly by mobile genetic elements, considered to be natural vectors of horizontal gene transfer. Transposable elements (TEs) play a major role in this process-due to their highly recombinogenic nature they can mobilize adjacent genes and can introduce them into the pool of mobile DNA. Studies investigating this phenomenon usually focus on the genetic load of transposons and the molecular basis of their mobility. However, genes introduced into evolutionarily distant hosts are not necessarily expressed. As a result, bacterial genomes contain a reservoir of transcriptionally silent genetic information that can be activated by various transposon-related recombination events. The TEs themselves along with processes associated with their transposition can introduce promoters into random genomic locations. Thus, similarly to integrons, they have the potential to convert dormant genes into fully functional antibiotic resistance determinants. In this review, we describe the genetic basis of such events and by extension the mechanisms promoting the emergence of new drug-resistant bacterial strains.

Keywords: antibiotic resistance; antibiotic resistance determinants; gene activation; gene expression; insertion sequence; promoter delivery; transcriptionally silent genes; transposable elements; transposon.

Figure 1

The main structural types and specific properties of bacterial TEs: (a) Simplified view of the structural diversity of class I and class II transposons. IS—insertion sequence; tIS—transporter IS; MITE—miniature inverted-repeat transposable element. The class II Tns are represented here by a Tn3 family element; (b) duplication of a target site during transposition and generation of directly repeated sequences (DRs) flanking the inserted TE; (c) divided promoter of a TPase gene. After IS circularization, the −10 and −35 hexamers form a strong fusion promoter (P) enabling efficient TPase expression.

Figure 2

Promoters delivered or generated by TEs that enable or modulate the expression of nearby AR genes: (a,b) transposase gene promoters; (c–g) fusion and outward promoters; (h) antisense RNA promoters; (i) promoters within composite Tns. In the fusion and hybrid promoters, the −35 and −10 hexamers originate from the inserted IS and target DNA, respectively. See text for details.

Figure 3

TE-induced deletions leading to activation or modulation of expression of AR genes from distantly located promoters. Deletions generated by (a) homologous recombination; (b) intramolecular replicative transposition; (c) transposition of IS21-family members; (d) conservative transposition; (e) IS excision enhancer protein. ARG—antibiotic resistance gene; IEE—IS excision enhancer protein. Symbols are identical to those in Figure 2. See text for details.

Figure 4

Periodic activation of a transcriptionally silent AR gene by promoters delivered through the formation of cointegrates. ARG—antibiotic resistance gene; P—promoter. Replicative transposition of an IS results in formation of a cointegrate between the IS (and promoter) donor and ARG-containing recipient replicons. Homologous recombination leads to resolution of the cointegrate plasmid into two independent IS-containing replicons. Further IS homology directed recombination events lead to the generation of a cointegrate replicon to produce the AR phenotype.

Figure 5

Promoters enabling or modulating the expression of AR genes transferred within Tns: (a,b) fusion and outward IS promoters within composite Tns; (c) internal promoters within non-composite Tns; (d) outward IS promoters within TMo/ISCR elements. See text for details. Symbols are identical to those used in Figure 2.