Submitted to: Journal of Antibiotics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/27/2003
Publication Date: 5/20/2003
Citation: CREEMER, L.C., BEIER, R.C., KIEHL, D.E. FACILE SYNTHESIS OF TILMICOSIN AND TYLOSIN RELATED HAPTENS FOR USE AS PROTEIN CONJUGATES. JOURNAL OF ANTIBIOTICS. 2003. v. 56(5). p. 481-487. Interpretive Summary: Tilmicosin and tylosin are antibiotics approved for veterinary use in the U.S. Tilmicosin is used for cattle, swine, and poultry to combat respiratory disease. It is also used with sheep in various areas of the world. Tilmicosin accumulates in bovine lung tissue. We would like to produce monoclonal antibodies to these antibiotics. Antibodies are substances that are produced by the immune system in response to foreign substances, which enter the body. The antibodies could be used to investigate the potential sites of tissue binding in the lung. Here we make derivatives of tilmicosin and tylosin that may be attached to immunogenic proteins (proteins that are recognized by the immune system) useful for antibody production. Since tylosin is acid labile and easily reacts to form unwanted products, steps were taken to remedy the problem. The derivative of tilmicosin was tested against 22 strains of bacteria to obtain the minimum inhibitory concentrations (MICs), and compared to the antibiotics tilmicosin and cephalothin. Derivatives of both tilmicosin and tylosin were made that are suitable for use in antibody production.
Technical Abstract: Synthesis is described for the haptens 23-demycinosyl-23-deoxo-23-(1, 3-diaminoprop-1-yl)-tilmicosin (6) from 5-O-mycaminosyltylonolide (OMT) and for 23-deoxy-23-(1, 3-diaminoprop-1-yl)-20-dihydrodemycinosyltylosin (10) from demycinosyltylosin (DMT), respectively. The mild reaction conditions used to synthesize the second hapten, the DMT derivative 10, were necessary to overcome instabilities and acid lability of DMT. The haptens synthesized here may further be used to produce protein conjugates useful in developing antibodies against the antibiotics tilmicosin and tylosin. The MICs of the hapten 6 against 22 strains of bacteria are compared to both tilmicosin and cephalothin. All organisms were less susceptible to 6 than they were to the positive control cephalothin, except for the avian bacterial strain Salmonella enteriditis, they were less susceptible to 6 than tilmicosin.