Recognition of Drug Degradation Products by Target Proteins: Isotetracycline Binding to Tet Repressor

• Published in: Journal of medicinal chemistry Vol. 54; no. 14; pp. 5108 - 5115
• Main Authors: Volkers, Gesa, Petruschka, Lothar, Hinrichs, Winfried
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.07.2011
• Subjects: Allosteric Regulation; Anti-Bacterial Agents - chemistry; Crystallography, X-Ray; Models, Molecular; Protein Binding; Protein Conformation; Recombinant Proteins - chemistry; Repressor Proteins - chemistry; Surface Plasmon Resonance; Tetracycline Resistance; Tetracyclines - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200332e

Tetracycline antibiotics and their degradation products appear in medically treated tissues, food, soil, and manure sludge in the environment. In the context of protein interactions with various tetracyclines we performed crystal structure analyses of the tetracycline repressor in complex with weak or noninducing tetracycline derivatives. Isotetracyclines are degradation products of tetracyclines, which occur under physiological conditions. The typical framework of the antibiotic is irreversibly broken at the BC-ring connection, leading to a modified orientation of the AB to the new C*D ring fragments. The shape of the zwitterionic AB-ring fragment is unchanged and still binds to the TetR recognition site in a manner comparable to the intact antibiotic but without typical Mg2+ chelation. This work is an example that drug degradation products can still bind to specific targets and should be discussed in light of potential and critical side effects.