Mechanism of the Fluoroquinolone Resistance Acquisition in Enterobacteria

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ABSTRACT Recent pandemic spread of antimicrobial resistance is highly alarming. Fluoroquinolones (FQ) are broadly used by clinicians for treatment of urinary tract infections, but FQ resistance levels in Escherichia coli (the main uropathogen) are reaching 15-35%. FQ targets DNA gyrase (GyrAB) and topoisomerase IV (ParCE), complexes that ensure maintenance of nucleoid super-coiling and structure in states appropriate for replication and partitioning. The FQ resistance acquisition primarily emerges by structural alteration of the target proteins with multiple mutations in so-called quinolone-resistance determining regions (QRDR) - two mutations in GyrA (usually Ser83Leu and Asp87Asn) that are tightly coupled to the presence of at least one mutation in ParC (usually Ser80Ile). We hypothesize that some clinical E. coli strains are more prone than others to acquire and, also, to spread or transmit the FQ resistance. Surprisingly, the most common uropathogenic groups of E. coli appear to demonstrate certain restraints to becoming FQ resistant, probably due to some physiological barriers for the sequential structural alteration of GyrA and ParC. We discovered that, instead, that urinary FQ resistant isolates can emerge by acquisition of genes already carrying the full set of QRDR changes, demonstrating for the first time that high-level FQ resistance can be transmitted between clinical strains of unrelated clonal groups. This, for example, was the mechanism of recent emergence of new pandemic FQ resistant clonal group of E. coli – ST1193 that spread globally with last decade. Here we will study whether there is a clonal association between the ability of clinical E. coli strains to acquire and spread in nature the full set of QRDR mutations sequentially or, alternatively, by gene transfer and what could be potential physiological factors that either promote or restrain the FQ resistance emergence, transmission and spread among uropathogenic E. coli.