Quinolones are widely used antimicrobial agents because of their broad antibacterial spectrum, low toxicity, and reliable action against otherwise resistant pathogens. Bacterial resistance to quinolones, however, is increasing and has reached alarming levels in some parts of Europe and the Far East. Various chromosomal mutations contribute to this resistance. Plasmid-mediated resistance was long thought not to exist. We discovered a plasmid-encoded protein termed Qnr that protects DNA gyrase from quinolone inhibition. Qnr acts additively with chromosomal mechanisms for quinolone resistance, belongs to the pentapeptide repeat family of proteins and, by a gel displacement assay, binds to the gyrase tetramer as well as to the GyrA and GyrB subunits with differing affinities. Although initially found in a limited number of isolates in the United States, the qnr gene has recently been discovered in a larger group of isolates from the Far East.
The aims of this proposal are: to elucidate the structural requirements for Qnr binding to gyrase, to establish the gyrase activities that Qnr can protect from quinolone inhibition, to determine whether Qnr can also protect the related quinolone target topoisomerase IV, to explore the hypothesis that Qnr blocks quinolone binding to gyrase, to study Qnr binding quantitatively using surface plasmon resonance, to investigate whether Qnr can also protect gyrase from such protein inhibitors as MccB17, CcdB, and Gyrl, to determine whether Qnr and an active gyrase fragment can co-crystallize for structural analysis by x-ray diffraction, and to study the detailed molecular structure of Qnr plasmids to elucidate how this novel property has been acquired. Qnr prevalence will also be explored utilizing samples from parts of the world where quinolone resistance has become common and also from food animal sources. These studies are important not only for understanding an emerging resistance mechanism but should also reveal details of how DNA gyrase and related topoisomerases function and how proteins in the pentapeptide family interact with and regulate the activity of other proteins. ? ?
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