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Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase


Antimicrobial-modifying resistance enzymes have traditionally been class specific, having coevolved with the antibiotics they inactivate. Fluoroquinolones, antimicrobial agents used extensively in medicine and agriculture, are synthetic and have been considered safe from naturally occurring antimicrobial-modifying enzymes. We describe reduced susceptibility to ciprofloxacin in clinical bacterial isolates conferred by a variant of the gene encoding aminoglycoside acetyltransferase AAC(6′)-Ib. This enzyme reduces the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent. Although approximately 30 variants of this gene have been reported since 1986, the two base-pair changes responsible for the ciprofloxacin modification phenotype are unique to this variant, first reported in 2003 and now widely disseminated. An intense increase in the medical use of ciprofloxacin seems to have been accompanied by a notable development: a single-function resistance enzyme has crossed class boundaries, and is now capable of enzymatically undermining two unrelated antimicrobial agents, one of them fully synthetic.

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Figure 1: Sequence alignment of eight different aac(6′)-Ib variants and aac(6′)-Ib-cr.
Figure 2: Enzyme kinetics of AAC(6′)-Ib-cr.
Figure 3: Mutant prevention concentration (MPC) assay.

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The authors thank Y. Onodera for suggestions, A. Maden for conducting the liquid chromatography–mass spectroscopy experiments and D. Mills and V. Walker for technical assistance. This study was supported in part by grants AI57576 (to D.C.H.) and AI43312 (to G.A.J.) from the National Institutes of Health, US Public Health Service.

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Correspondence to David C Hooper.

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Mark Macielag, Darren Abbanat and Karen Bush are employees of Johnson & Johnson Pharmaceutical Research and Development. George A. Jacoby is supported by a research grant from Merck & Co. David C. Hooper is supported by research grants from Daiichi Pharmaceuticals.

Supplementary information

Supplementary Fig. 1

Integron sequence of plasmid pHSH10-2. (PDF 138 kb)

Supplementary Fig. 2

RP-HPLC elution profiles. (PDF 164 kb)

Supplementary Table 1

Clone designations for the site-directed mutagenesis study. (PDF 16 kb)

Supplementary Table 2

Primers used in the site-directed mutagenesis study. (PDF 15 kb)

Supplementary Methods (PDF 55 kb)

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Robicsek, A., Strahilevitz, J., Jacoby, G. et al. Fluoroquinolone-modifying enzyme: a new adaptation of a common aminoglycoside acetyltransferase. Nat Med 12, 83–88 (2006).

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