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Antimicrobial Agents and Chemotherapy, August 2007, p. 2820-2829, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00087-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Chloramphenicol Is a Substrate for a Novel Nitroreductase Pathway in Haemophilus influenzae

Arnold L. Smith,^1,2,3* Alice L. Erwin,^1, Toni Kline,⁴ William C. T. Unrath,¹ Kevin Nelson,¹ Allan Weber,^2, and William N. Howald⁵

Microbial Pathogens Program, Seattle Biomedical Research Institute, Seattle, Washington 98109,¹ Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri 65197,² Departments of Pathobiology,³ Genome Sciences,⁴ Medicinal Chemistry, University of Washington, Seattle, Washington 98195⁵

Received 19 January 2007/ Returned for modification 15 February 2007/ Accepted 30 April 2007

The p-nitroaromatic antibiotic chloramphenicol has been used extensively to treat life-threatening infections due to Haemophilus influenzae and Neisseria meningitidis; its mechanism of action is the inhibition of protein synthesis. We found that during incubation with H. influenzae cells and lysates, chloramphenicol is converted to a 4-aminophenyl allylic alcohol that lacks antibacterial activity. The allylic alcohol moiety undergoes facile re-addition of water to restore the 1,3-diol, as well as further dehydration driven by the aromatic amine to form the iminoquinone. Several Neisseria species and most chloramphenicol-susceptible Haemophilus species, but not Escherichia coli or other gram-negative or gram-positive bacteria we examined, were also found to metabolize chloramphenicol. The products of chloramphenicol metabolism by species other than H. influenzae have not yet been characterized. The strains reducing the antibiotic were chloramphenicol susceptible, indicating that the pathway does not appear to mediate chloramphenicol resistance. The role of this novel nitroreductase pathway in the physiology of H. influenzae and Neisseria species is unknown. Further understanding of the H. influenzae chloramphenicol reduction pathway will contribute to our knowledge of the diversity of prokaryotic nitroreductase mechanisms.

Published ahead of print on 25 May 2007.

Present address: Vertex Pharmaceuticals, Inc., Cambridge, MA 02139.

Present address: Department of Pharmacokinetics and Drug Metabolism, Allergan Pharmaceuticals, Irvine, CA 92612.