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Antimicrobial Agents and Chemotherapy, June 2006, p. 2156-2166, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.01499-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline

Matthew W. Olson ,1,{dagger},{ddagger} Alexey Ruzin,2,{dagger}* Eric Feyfant,3,{dagger} Thomas S. Rush III,3,§ John O'Connell,2 and Patricia A. Bradford2

Department of Chemical and Screening Sciences, Wyeth Research, Pearl River, New York 10965,1 Department of Infectious Disease, Wyeth Research, Pearl River, New York 10965,2 Departments of Computational Chemistry and Structural Biology, Wyeth Research, Cambridge, Massachusetts 021403

Received 21 November 2005/ Returned for modification 20 January 2006/ Accepted 9 March 2006

Tigecycline is a novel glycylcycline antibiotic that possesses broad-spectrum activity against many clinically relevant species of bacterial pathogens. The mechanism of action of tigecycline was delineated using functional, biophysical, and molecular modeling experiments in this study. Functional assays showed that tigecycline specifically inhibits bacterial protein synthesis with potency 3- and 20-fold greater than that of minocycline and tetracycline, respectively. Biophysical analyses demonstrated that isolated ribosomes bind tigecycline, minocycline, and tetracycline with dissociation constant values of 10–8, 10–7, and >10–6 M, respectively. A molecular model of tigecycline bound to the ribosome was generated with the aid of a 3.40-angstrom resolution X-ray diffraction structure of the 30S ribosomal subunit from Thermus thermophilus. This model places tigecycline in the A site of the 30S subunit and involves substantial interactions with residues of H34 of the ribosomal subunit. These interactions were not observed in a model of tetracycline binding. Modeling data were consistent with the biochemical and biophysical data generated in this and other recent studies and suggested that tigecycline binds to bacterial ribosomes in a novel way that allows it to overcome tetracycline resistance due to ribosomal protection.

* Corresponding author. Mailing address: Wyeth Research, Department of Infectious Disease, 401 North Middletown Road, Bldg. 200, Rm. 3218, Pearl River, NY 10965. Phone: (845) 602-4592. Fax: (845) 602-5671. E-mail: ruzina{at}wyeth.com.

{dagger} These authors contributed to this work equally.

{ddagger} Present address: Johnson & Johnson Pharmaceutical Research & Development, 665 Stockton Drive, Exton, PA 19341.

§ Present address: Department of Medicinal Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115.

Antimicrobial Agents and Chemotherapy, June 2006, p. 2156-2166, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.01499-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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