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

Abstract

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.

References

  1. Nikaido, H. Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264, 382–388 (1994).

    CAS  Article  Google Scholar 

  2. Pechère, J.C. Macrolide resistance mechanisms in gram-positive cocci. Int. J. Antimicrob. Agents 18 Suppl. 1, S25–S28 (2001).

    Article  Google Scholar 

  3. Wang, F., Zhu, D., Hu, F. & Zhang, Y. Surveillance of bacterial resistance among isolates in Shanghai in 1999. J. Infect. Chemother. 7, 117–120 (2001).

    CAS  Article  Google Scholar 

  4. Wetzstein, H.G., Schmeer, N. & Karl, W. Degradation of the fluoroquinolone enrofloxacin by the brown rot fungus Gloeophyllum striatum: identification of metabolites. Appl. Environ. Microbiol. 63, 4272–4281 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang, M. et al. Plasmid-mediated quinolone resistance in clinical isolates of Escherichia coli from Shanghai, China. Antimicrob. Agents Chemother. 47, 2242–2248 (2003).

    CAS  Article  Google Scholar 

  6. Wang, M., Sahm, D.F., Jacoby, G.A. & Hooper, D.C. Emerging plasmid-mediated quinolone resistance associated with the qnr gene in Klebsiella pneumoniae clinical isolates in the United States. Antimicrob. Agents Chemother. 48, 1295–1299 (2004).

    CAS  Article  Google Scholar 

  7. Robicsek, A., Sahm, D.F., Strahilevitz, J., Jacoby, G.A. & Hooper, D.C. Broader distribution of plasmid-mediated quinolone resistance in the United States. Antimicrob. Agents Chemother. 49, 3001–3003 (2005).

    CAS  Article  Google Scholar 

  8. Tolmasky, M.E., Roberts, M., Woloj, M. & Crosa, J.H. Molecular cloning of amikacin resistance determinants from a Klebsiella pneumoniae plasmid. Antimicrob. Agents Chemother. 30, 315–320 (1986).

    CAS  Article  Google Scholar 

  9. Domagala, J.M. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J. Antimicrob. Chemother. 33, 685–706 (1994).

    CAS  Article  Google Scholar 

  10. Heisig, P. & Tschorny, R. Characterization of fluoroquinolone-resistant mutants of Escherichia coli selected in vitro. Antimicrob. Agents Chemother. 38, 1284–1291 (1994).

    CAS  Article  Google Scholar 

  11. Neuhauser, M.M. et al. Antibiotic resistance among gram-negative bacilli in US intensive care units - Implications for fluoroquinolone use. J. Am. Med. Assoc. 289, 885–888 (2003).

    CAS  Article  Google Scholar 

  12. Martinez-Freijo, P. et al. Class I integrons in gram-negative isolates from different European hospitals and association with decreased susceptibility to multiple antibiotic compounds. J. Antimicrob. Chemother. 42, 689–696 (1998).

    CAS  Article  Google Scholar 

  13. Boyd, D.A. et al. Complete nucleotide sequence of a 92-kilobase plasmid harboring the CTX-M-15 extended-spectrum beta-lactamase involved in an outbreak in long-term-care facilities in Toronto, Canada. Antimicrob. Agents Chemother. 48, 3758–3764 (2004).

    CAS  Article  Google Scholar 

  14. Vetting, M.W., Magnet, S., Nieves, E., Roderick, S.L. & Blanchard, J.S. A bacterial acetyltransferase capable of regioselective N-acetylation of antibiotics and histones. Chem. Biol. 11, 565–573 (2004).

    CAS  Article  Google Scholar 

  15. Bennett, A.D. & Shaw, W.V. Resistance to fusidic acid in Escherichia coli mediated by the type I variant of chloramphenicol acetyltransferase. Biochem. J. 215, 29–38 (1983).

    CAS  Article  Google Scholar 

  16. Murray, I.A. et al. Steroid recognition by chloramphenicol acetyltransferase: engineering and structural analysis of a high affinity fusidic acid binding site. J. Mol. Biol. 254, 993–1005 (1995).

    CAS  Article  Google Scholar 

  17. Davies, J.E. Aminoglycoside-aminocyclitol antibiotics and their modifying enzymes. in Antibiotics in Laboratory Medicine (ed. Lorian, V.), 790–809 (Williams & Wilkins, Baltimore, 1986).

    Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/nm1347

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