Vol.53 No.6 June 2005
History of mode of action and resistance mechanisms of quinolones
Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd.,
2-5 Kanda Surugadai, Chiyoda-ku, Tokyo, Japan
Abstract
Many new quinolones, namely fluoro-quinolones, have been developed since norfloxacin (NFLX) was discovered in 1978. These drugs became useful medicine for various infectious diseases including pneumonia. The researches on mode of action of quinolone and resistant mechanisms have been made great advances with the progression of these new quinolones. In this review, I would like to introduce the progress of studies on mode of action of quinolones and mechanisms of quinolone-resistance in bacteria from mid 1970s.
1. Mode of action: Target enzymes: DNA gyrase and Topoisomerase IV:
It was known that quinolones inhibit DNA replication in Escherichia coli, however, detailed mode of action was not clarified when we started the research and development of new quinolones. DNA gyrase was identified as the target enzyme of quinolone in 1977. Afterward, researches on mechanism of actions of quinolones have been made a remarkable progress using various new quinolones such as norfloxacin. Consequently, interesting findings were reported such as formation of cleavable complex (DNA gyrase-DNA-Quinolone) by quinolone, quinolone resistance-determining region (QRDR), and structure-activity relationship for various DNA gyrase in bacteria. In 1990, new target, namely Topoisomerase IV, of quinolone other than DNA gyrase was identified. This enzyme was showed to involve with antibacterial activity of quinolones especially respiratory quinolones and quinolone-resistance mechanisms in Gram-positive bacteria.
2. Quinolone-resistance mechanisms involved in membrane:
We found that quinolone-resistant mechanisms were due to alterations in DNA gyrase and in cell permeability of outer membrane proteins in E. coli and Pseudomonas aeruginosa. In E. coli, it was suggested that quinolone might penetrate through the OmpF porin, and alterations in permeability to quinolones in members of the Enterobacteriaceae have been associated with the decrease of specific outer membrane proteins. We isolated three types of norfloxacin resistant mutants, nfxB, nfxC, and nalB, showed alteration in membrane permeability associated with the appearance and/or increase of outer membrane proteins. Using these mutants, it was found that these mutations activated efflux pumps in P. aeruginosa, and these data suggested efflux pumps might play an important role in resistance for various antibacterial agents in P. aeruginosa.
More recently, plasmid-mediated quinolone-resistance in Gram-negative bacteria was found in US and China. These finding might be very critical for spread of quinolone-resistant genes by plasmids, therefore we will have to keep watch on this type quinolone-resistance.
Key word
drug-resistance, mode of action, DNA gyrase, efflux pump
Received
February 4, 2005
Accepted
April 7, 2005
Jpn. J. Chemother. 53 (6): 349-356, 2005
