Quinolones are widely used antimicrobial agents because of their broad antibacterial spectrum and reliable action against otherwise resistant bacteria. Quinolone resistance has been slowly but steadily increasing. It has been previously shown that various chromosomal mutations contribute to this resistance, but plasmid-mediated resistance has not been shown to occur. The Principal Investigator has discovered a 56 kb, broad host range, multiresistance plasmid in clinical isolates of Klebsiella pneumoniae and Escherichia coli that confers quinolone resistance in a variety of gram negative bacteria. The level of plasmid-mediated quinolone resistance is low in wild-type E. coli, but higher degrees of quinolone resistance can be selected for when the plasmid is present. The quinolone resistance (qnr) locus has been cloned and sequenced from the 56 kb plasmid. The nucleotide sequence is unique, but the predicted protein (termed Qnr) has similarity to the microcin B17 immunity protein which protects DNA gyrase from microcin inhibition.
The aims of the proposal are to identify the qnr promoter by sequencing the 5' end of its mRNA, to construct a high level expression and purification system for Qnr, to study the ability of purified Qnr to protect DNA gyrase and topoisomerase IV from quinolone inhibition, to explore binding of Qnr to these quinolone targets and their subunits, and to establish the prevalence of qnr mediated resistance, both at the hospital where it was first detected and in samples of resistant bacteria from other sources. Understanding how qnr acts may help to curtail the rise in quinolone resistance and may also provide fundamental insights into aspects of DNA replication.
| Kim, Hong Bin; Park, Chi Hye; Gavin, Mariah et al. (2011) Cold shock induces qnrA expression in Shewanella algae. Antimicrob Agents Chemother 55:414-6 |
| Kim, Hong Bin; Wang, Minghua; Ahmed, Sabeena et al. (2010) Transferable quinolone resistance in Vibrio cholerae. Antimicrob Agents Chemother 54:799-803 |
| Wang, Minghua; Jacoby, George A; Mills, Debra M et al. (2009) SOS regulation of qnrB expression. Antimicrob Agents Chemother 53:821-3 |
| Jacoby, George A; Gacharna, Nancy; Black, Todd A et al. (2009) Temporal appearance of plasmid-mediated quinolone resistance genes. Antimicrob Agents Chemother 53:1665-6 |
| Kim, Hong Bin; Wang, Minghua; Park, Chi Hye et al. (2009) oqxAB encoding a multidrug efflux pump in human clinical isolates of Enterobacteriaceae. Antimicrob Agents Chemother 53:3582-4 |
| Strahilevitz, Jacob; Jacoby, George A; Hooper, David C et al. (2009) Plasmid-mediated quinolone resistance: a multifaceted threat. Clin Microbiol Rev 22:664-89 |
| Kim, Hong Bin; Park, Chi Hye; Kim, Chung Jong et al. (2009) Prevalence of plasmid-mediated quinolone resistance determinants over a 9-year period. Antimicrob Agents Chemother 53:639-45 |
| Vetting, Matthew W; Park, Chi Hye; Hegde, Subray S et al. (2008) Mechanistic and structural analysis of aminoglycoside N-acetyltransferase AAC(6')-Ib and its bifunctional, fluoroquinolone-active AAC(6')-Ib-cr variant. Biochemistry 47:9825-35 |
| Jacoby, George; Cattoir, Vincent; Hooper, David et al. (2008) qnr Gene nomenclature. Antimicrob Agents Chemother 52:2297-9 |
| Whichard, Jean M; Gay, Kathryn; Stevenson, Jennifer E et al. (2007) Human Salmonella and concurrent decreased susceptibility to quinolones and extended-spectrum cephalosporins. Emerg Infect Dis 13:1681-8 |
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