A <i>qnr</i>-plasmid allows aminoglycosides to induce SOS in <i>Escherichia coli</i>.

Abstract

The plasmid-mediated quinolone resistance (PMQR) genes have been shown to promote high-level bacterial resistance to fluoroquinolone antibiotics, potentially leading to clinical treatment failures. In <i>Escherichia coli</i>, sub-minimum inhibitory concentrations (sub-MICs) of the widely used fluoroquinolones are known to induce the SOS response. Interestingly, the expression of several PMQR <i>qnr</i> genes is controlled by the SOS master regulator, LexA. During the characterization of a small <i>qnrD</i>-plasmid carried in <i>E. coli,</i> we observed that the aminoglycosides become able to induce the SOS response in this species, thus leading to the elevated transcription of <i>qnrD</i>. Our findings show that the induction of the SOS response is due to nitric oxide (NO) accumulation in the presence of sub-MIC of aminoglycosides. We demonstrated that the NO accumulation is driven by two plasmid genes, ORF3 and ORF4, whose products act at two levels. ORF3 encodes a putative flavin adenine dinucleotide (<i>FAD</i>)-binding oxidoreductase which helps NO synthesis, while ORF4 codes for a putative fumarate and nitrate reductase (<i>FNR</i>)-type transcription factor, related to an O₂-responsive regulator of <i>hmp</i> expression, able to repress the Hmp-mediated NO detoxification pathway of <i>E. coli</i>. Thus, this discovery, that other major classes of antibiotics may induce the SOS response could have worthwhile implications for antibiotic stewardship efforts in preventing the emergence of resistance.