Fluoroquinolones resistance by target protection
Resistance mechanisms originating from bacterial population of water bodies are less well documented than from soil organisms. However, the significance of water bodies as natural source for resistance mechanisms is similar compared to the soil. For example, a well known example is provided by the acquired fluoroquinolones resistance genes of the qnr family. qnr genes encode proteins binding the bacterial DNA gyrase, thus preventing the interaction of the antibiotic with its target. Generally, the presence of these acquired genes does not confer a high level of fluoroquinolones resistance, but provides a selective advantage in the presence of these drugs, even at low concentrations (Rodriguez-Martinez et al., 2011). Further, this protecting mechanism and the associated low level resistance may favor the emergence of strains with higher resistances to fluoroquinolones by mutations in the QRDR, quinolones resistance determining region, and/or by over-expressing efflux systems. Several aquatic bacterial species have been proposed as progenitors for these genes families. Poirel et al. (2005b) reported evidences that the qnrA gene located on plasmids and found in clinical isolates of fluoroquinolones resistant Enterobacteriaceae, is derived from the chromosome of Shewanella algae, a bacterial species present in marine and freshwater. The authors advanced the hypothesis that the gene jumped from the environmental species to Enterobacteriaceae probably under pressure of antibiotic usage. Beaber et al. (2004) have demonstrated that the presence of fluoroquinolones induces the SOS bacterial repair system, which in turn promotes horizontal gene transfer. Poirel et al. (2005a) conducted further investigations in order to understand the origin of this antibiotic resistance mechanism. Their study highlighted that the chromosomes of water borne bacteria, Vibrio vulnificus, Vibrio parahaemolyticus, and Photobacterium profundum harbored qnr-like genes with homology (40–67% identity) to the plasmidic qnrA, qnrB, and qnrS genes described in clinical Enterobacteriaceae.
Interestingly, qnrA has been observed frequently associated with the insertion sequence ISCR1, a genetic element able to mobilize adjacent genes. Toleman et al. (2006) hypothesized that the ISCR1 mediated mobilization of qnrA, as well as a further localization on a class 1 integron to form a so-called complex integron structure. The authors formulated that this complex integron structure is responsible for the successful dissemination of qnrA gene. Arsène and Leclercq (2007) investigated the intrinsic resistance of E. faecalis to fluoroquinolones and found that this species is provided with a chromosomal qnr-like gene, which contributes to resistance against fluoroquinolones. Soon afterward, Sánchez et al. (2008) discovered that the aquatic bacterium S. maltophilia is a sink of qnr genes and the chromosomally located Smqnr gene identified in this species is able to confer resistance to fluoroquinolones in heterologous species. In 2010, Velasco et al. (2010) reported qnr-like genes from Serratia marcescens, an environmental species. These genes, called Smaqnr, were largely present in the chromosome of the genus. Recently, Jacoby et al. (2011) have highlighted that the Citrobacter spp. chromosome constitutes a reservoir for the qnrB fluoroquinolones resistance gene. The presence of qnr genes on the chromosome of phylogenetically distant bacterial species (Shewanella, Stenotrophomonas, Vibrio, Enterococcus, Serratia, Citrobacter), suggests an ancestral role of this antibiotic resistance mechanism. Hernandez et al. (2011b) postulated a regulatory role for the Qnr proteins. Indeed, by interacting with the DNA gyrase, Qnr may protect the DNA gyrase against toxic DNA substances and indirectly modulate gene expression in response to environmental changes. Moreover, a beneficial role of these protecting mechanisms has been shown for qnrA3, which confers a fitness advantage to the bacteria, favoring its dissemination. The fitness advantage was found abolished when qnrA3 was carried by large multi-drug resistance plasmids (Michon et al., 2011). The activation of qnrB expression by the SOS-response system could also have an implication in the conservation of such mechanism. As ciprofloxacin induces the SOS-response system, it activates its corresponding resistance mechanisms (Da Re et al., 2009). Several studies have reported qnr genes in heterologous species from water habitats. Cattoir et al. (2008) recovered from the Seine River A. punctata and A. media harboring qnrS2. Similarly, Picao et al. (2008) detected qnrS genes in Aeromonas allosaccarophila from the Lugano Lake, in Switzerland. A qnrVC4 allele was isolated from aquatic environments in A. punctata by Xia et al. (2010). All these reports demonstrate that the Aeromonas genus represents a reservoir for fluoroquinolones resistance mediated by Qnr. Our own studies characterized a qnrS determinant in E. coli belonging to ST131 isolated from freshwater of a Ukrainian River (Lupo et al., submitted). Similarly, Dhanji et al. (2011) isolated E. coli strains belonging to ST131 harboring a qnrS allele from the Thames River (Table 1). These findings reflect a spread of these resistance mechanisms by geographical and clonal means and highlight the potential of rivers in the dissemination of international resistant clones.