Journal of Antimicrobial Chemotherapy, Vol 39, 697-705, Copyright © 1997 by The British Society for Antimicrobial Chemotherapy
J Mitsuyama, H Yamada, J Maehana, Y Fukuda, S Kurose, S Minami, Y Todo, Y Watanabe and H Narita
Exposure of Staphylococcus aureus to 1 x MIC of the quinolone antibiotic
pazufloxacin for 24 h, followed by plating on drug-free media, led to the
emergence of small colony variants (SCVs) in addition to large colony
variants (LCVs). However, following incubation with 0.25 or 4 x MIC of
pazufloxacin, only LCVs were obtained. The SCVs were half as susceptible to
pazufloxacin or ciprofloxacin as wild-type S. aureus, while the
susceptibilities of LCVs were essentially unchanged. The reduced
susceptibilities of SCVs did not result from mutations in the
quinolone-resistance-determining regions of DNA gyrase and topoisomerase
IV, since the sequences of these genes were identical to those of the
wild-type. However, the SCVs accumulated pazufloxacin and ciprofloxacin to
a lesser degree than did wild-type. Furthermore, their susceptibility to
quinolones was almost unaffected by reserpine or verapamil, suggesting that
the reduced uptake resulted from decreased permeability, rather than from
an active efflux pump. The ability of various quinolones to induce
emergence of SCVs in S. aureus, correlated with the presence of
carbon-bonded substituents at the C-7 position of a quinoline or
naphthyridine nucleus, or with the presence of a benzoxazine nucleus. In
conclusion, pazufloxacin-induced SCVs represent a mutant that one might
expect to be rapidly eliminated in vivo and, hence, not to survive as a
quinolone-resistant pathogen. This finding suggests a novel approach for
development of future quinolones.
JOURNAL ARTICLE
Characteristics of quinolone-induced small colony variants in Staphylococcus aureus
Research Laboratories of Toyama Chemical Co., Ltd., Toyama City, Japan.
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