Abstract
Dissemination of antibiotic resistance genes occurs mostly by conjugation, which mediates DNA transfer between cells in direct contact. Conjugative plasmids of the IncA/C incompatibility group have become a substantial threat due to their broad host-range, the extended spectrum of antimicrobial resistance they confer, their prevalence in enteric bacteria and their very efficient spread by conjugation. However, their biology remains largely unexplored. Using the IncA/C conjugative plasmid pVCR94ΔX as a prototype, we have investigated the regulatory circuitry that governs IncA/C plasmids dissemination and found that the transcriptional activator complex AcaCD is essential for the expression of plasmid transfer genes. Using chromatin immunoprecipitation coupled with exonuclease digestion (ChIP-exo) and RNA sequencing (RNA-seq) approaches, we have identified the sequences recognized by AcaCD and characterized the AcaCD regulon. Data mining using the DNA motif recognized by AcaCD revealed potential AcaCD-binding sites upstream of genes involved in the intracellular mobility functions (recombination directionality factor and mobilization genes) in two widespread classes of genomic islands (GIs) phylogenetically unrelated to IncA/C plasmids. The first class, SGI1, confers and propagates multidrug resistance in Salmonella enterica and Proteus mirabilis, whereas MGIVmi1 in Vibrio mimicus belongs to a previously uncharacterized class of GIs. We have demonstrated that through expression of AcaCD, IncA/C plasmids specifically trigger the excision and mobilization of the GIs at high frequencies. This study provides new evidence of the considerable impact of IncA/C plasmids on bacterial genome plasticity through their own mobility and the mobilization of genomic islands.
Highlights
Multidrug resistance (MDR) is steadily increasing in Gramnegative bacteria in both community and hospital settings, and represents a growing concern worldwide [1]
We have found that AcaCD, the master activator complex encoded by these plasmids, is essential for the dissemination of IncA/C plasmids and activates unrelated mobile genetic elements in bacterial genomes, thereby further promoting the interspecies propagation of multidrug resistance and other adaptive traits at a very high frequency
Identification of repressors of IncA/C plasmids transfer Comparative genomics previously revealed a set of six genes coding for putative transcriptional regulators in pVCR94 that are conserved in most IncA/C plasmids [19] (Table S1)
Summary
Multidrug resistance (MDR) is steadily increasing in Gramnegative bacteria in both community and hospital settings, and represents a growing concern worldwide [1]. Conjugative plasmids of the IncA/C incompatibility group, which are prevalent in enteric bacteria, have become a substantial threat due to their broad host-range, their extended spectrum of antimicrobial resistance and their efficient spread by conjugation [2]. Several IncA/C plasmids are spreading the New Delhi metallo-lactamase blaNDM-1 gene and its variants, which confer resistance to all blactams except for monobactams and are widely distributed throughout all Gammaproteobacteria [5,6,7,8]. Resistance to blactams, aminoglycosides, chloramphenicol, folate pathway inhibitors (sulfonamides and trimethoprim), quinolones and tetracycline is commonly conferred by these large plasmids IncA/C plasmids have been shown to mobilize in trans the Salmonella genomic island 1 (SGI1), a 43-kb chromosomal mobile element carrying a class 1 integron that confers resistance to ampicillin, chloramphenicol, streptomycin, Author Summary
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