Functional, biophysical, and structural bases for antibacterial activity of tigecycline.
Article Details
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Olson MW, Ruzin A, Feyfant E, Rush TS 3rd, O'Connell J, Bradford PA
Functional, biophysical, and structural bases for antibacterial activity of tigecycline.
Antimicrob Agents Chemother. 2006 Jun;50(6):2156-66.
- PubMed ID
- 16723578 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Tigecycline 16S ribosomal RNA Nucleotide Enteric bacteria and other eubacteria YesBinderDetails Tigecycline 30S ribosomal protein S12 Protein Escherichia coli (strain K12) YesBinderDetails Tigecycline 30S ribosomal protein S13 Protein Escherichia coli (strain K12) YesBinderDetails Tigecycline 30S ribosomal protein S14 Protein Escherichia coli (strain K12) YesBinderDetails Tigecycline 30S ribosomal protein S19 Protein Escherichia coli (strain K12) YesBinderDetails Tigecycline 30S ribosomal protein S9 Protein Escherichia coli (strain K12) YesBinderDetails