Posted March 13, 2010
The emergence of bacterial resistance has compromised the effectiveness of the antibiotic tetracycline, a natural product produced by soil bacteria that has stood in the front line against disease for more than 50 years. Its ready availability and low toxicity have made tetracycline a mainstay of treatment for a wide range of conditions, from acne to septicemia. Therefore, researchers are working to develop new tetracycline analogs—novel drugs that will combat infection while thwarting resistance, at least over the short term.
A provocative meeting of the Academy's Chemical Biology Discussion Group on November 30, 2005, featured talks by three researchers working to reinvent this multifaceted molecule. Topics discussed included efforts to create tetracycline-related therapeutics using biosynthetic and genetic engineering techniques, a review of the obstacles and triumphs involved in creating tigecycline, a member of new class of drugs called glycylcyclines, and insights into how tigecycline differs from tetracycline and related drugs.
Use the tabs above to view the meeting report and multimedia presentations.
MedLine Plus Drug Information
Consumer information on tetracycline.
Wyeth Phramaceuticals home page for the drug.
Khosla, C. & Y. Tang. 2005. A new route to designer antibiotics. Science 308: 367-368.
Kumar, P., C. Khosla & Y. Tang. 2004. Manipulation and analysis of polyketide synthases. Methods Enzymol. 388: 269-93.
Lee, T. S., C. Khosla & Y. Tang. 2005. Engineered biosynthesis of aklanonic acid analogs. J. Am. Chem. Soc. 127: 12254-12262. Full Text
Tang, Y, A. Koppisch & C. Khosla. 2004. The acyltransferase homolog found in initiation modules of type II PKS is an acetyl-ACP thiolase that suppresses acetate-priming of the KS-CLF. Biochemistry 43: 9546-9555.
Tang, Y., S. C.Tsai & C. Khosla. 2003. Polyketide chain length control by chain length factor. J. Am. Chem. Soc. 125: 12708-12709.
Tang, Y, T. S. Lee & C. Khosla. 2004. Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases. PLoS Biol. 2: 227-237. Full Text
Tang, Y, T. S. Lee, H. Y. Lee & C. Khosla. 2004. Exploring the biosynthetic potential of bimodular aromatic polyketide synthases. Tetrahedron 7659-7671.
Tang, Y., T. S. Lee, S. Kobayashi & C. Khosla. 2003. Ketosynthases in the initiation and elongation modules of aromatic polyketide synthases have orthogonal acyl-carrier protein specificity. Biochemistry 42: 6588-6595.
The Discovery of Tygacil
Dean, C., M. Visalli, S. J. Projan, et al. 2003. Efflux-mediated resistance to tigecycline in Pseudomonas aeruginosa. Antimicro. Agents Chemother. 47: 972-978. Full Text
Lederer, T., M. Kintrup, M. Takahashi, et al. 1996. Tetracycline analogs affecting binding to Tn10-encoded Tet Repressor trigger the same mechanism of induction. Biochemistry 35: 7439-7446.
Orth, P., D. Schnappinger, P.-E. Sum, et al. 1999. Crystal structure of the Tet repressor in complex with a novel tetracycline, 9-(N,N-dimethylglycylamido)-6-demethyl-6-deoxy-tetracycline. J. Mol. Biol. 285: 455-461.
Petersen, P. J., N. V. Jacobus, A. G. Shelofsky, et al. 1994. In vitro activity of a novel glycylcycline compound TBG-MINO. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
Petersen, P. J., N. V. Jacobus, W. J. Weiss, et al. 1999. In vitro and in vivo antibacterial activities of a novel glycylcycline, TBG-MINO (GAR-936). Antimicrob. Agents Chemother. 43: 738-744.
Sum, P.-E., A. Ross, P. Petersen & R. Testa. 2006. Synthesis and antibacterial activity of 9-substituted minocycline derivatives. Bioorg. Med. Chem. Lett. 16: 400-403.
Sum, P.-E., F.-W. Sum & S. J. Projan. 1998. Recent developments in tetracycline antibiotics. Curr. Pharm. Des. 4: 119-132.
Sum, P.-E. & P. J. Petersen. 1999. Synthesis and structure-activity relationships of novel glycylcycline derivatives leading to the discovery of GAR-936. Bioorg. Med. Chem. Lett. 9: 1459-1462.
Sum, P.-E., V. J. Lee & F. P. Tally. 1994. Synthesis of novel tetracycline derivatives with substitution at the C-8 position. Tetrahedron Lett. 35: 1835-1836.
Sum, P.-E., V. J. Lee, P. J. Petersen, et al. 1994. Novel glycylcycline derivatives: The design, synthesis and structure-activity relationships of 7-(substituted)-9-(substituted glycylamido)-6-demethyl-6-deoxytetracyclines. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).
Sum, P.-E., V. J. Lee, R. T. Testa, et al. 1994. "Glycylcyclines" I: a new generation of potent antibacterial agents through modification of 9-aminotetracyclines. J. Med. Chem. 37: 184-188.
Testa, R. T., P. J. Petersen, N. V. Jacobus, et al. 1993. In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines. Antimicro. Agents Chemother. 37: 2270-2277. Full Text
Tygacil, a Novel Glycylcycline Antibiotic
Bouchillon, S. K., D. J. Hoban, B. M. Johnson, et al. 2005. In vitro evaluation of tigecycline and comparative agents in 3,049 recent clinical isolates: 2001 to 2002. Diagn. Microbiol. Infect. Dis. 51: 291-295.
Bradford, P. A. 2004. Tigecycline: A novel first in class glycylcycline. Clin. Microbiol. Newslett. 26: 163-168.
Bradford, P. A., D. T. Weaver-Sands & P. J. Petersen. 2005. In vitro activity of tigecycline against isolates from patients enrolled in phase 3 clinical trials for complicated skin and skin structure infections and complicated intra-abdominal infections. Clin. Infect. Dis. 41: S315-S332.
Bradford, P. A., P. J. Petersen, M. Young, et al. 2005. MIC testing for tigecycline performed by broth dilution tests requires the use of fresh media or the addition of the biocatalytic oxygen-reducing reagent oxyrase to standardize the test method. Antimicrob. Agents. Chemother. 49: 3903-3909.
Jones, C. H., M. Tuckman, A. Y. M. Howe, et al. 2006. Occurrence of methicillin and tetracycline resistance genes among Staphylococcus aureus isolates from tigecycline phase 3 clinical trials for complicated skin and skin structure infections using diagnostic PCR analysis. Antimicrob. Agents. Chemother. 50: 505-510.
Labthavikul, P., P. J. Petersen & P. A. Bradford. 2003. In vitro activity of tigecycline against Staphylococcus epidermidis in an adherent-cell biofilm model. Antimicrob. Agents Chemother. 47: 3967-3969. Full Text
McAleese, F., E. Murphy, T. Babinchak, et al. 2005. Use of ribotyping and other molecular methods to identify potential strains of CA-MRSA isolated during phase 3 clinical trials for tigecycline. Antimicrob. Agents. Chemother. 49: 4521-4529.
McAleese, F. M., P. Petersen, A. Ruzin, et al. 2005. A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory derived Staphylococcus aureusmutants to tigecycline. Antimicrob. Agents Chemother. 49: 1865-1871. Full Text
Petersen, P. & P. A. Bradford. 2005. Effect of media age and supplementation with the biocatalytic oxygen-reducing reagent oxyrase on the in vitro activities of tigecycline against recent clinical isolates. Antimicrob. Agents. Chemother. 49: 3910-3918.
Ruzin, A., D. Keeney & P. A. Bradford. 2005. AcrAB efflux pump plays a role in decreased susceptibility to tigecycline in Morganella morganii. Antimicrob. Agents Chemother. 49: 791-793. Full Text
Ruzin, A., M. A. Visalli, D. Keeney & P. A. Bradford. 2005. Influence of transcriptional activator RamA on expression of multidrug efflux pump AcrAB and tigecycline susceptibility in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 49: 1017-1022. Full Text
Visalli, M. A., E. Murphy, S. J. Projan & P.A. Bradford. 2003. AcrAB multidrug efflux pump homolog is associated with reduced levels of susceptibility to tigecycline (GAR-93) in Proteus mirabilis. Antimicrob. Agents Chemother. 47: 665-669. Full Text
Yi Tang, PhD
Yi Tang is an assistant professor in the department of chemical engineering at the University of California, Los Angeles. He obtained his PhD in chemical engineering at the California Institute of Technology and went on to work as an NIH Postdoctoral Fellow at Stanford University. He has received numerous honors, including the National Science Foundation CAREER award, National Research Service Award, National Institute of Health; Whitaker Graduate Research Fellowship in Biomedical Engineering; Caltech 10K Business Plan Competition Winner; and Constantin Economou Award for Excellency in Graduate Research.
Phaik-Eng Sum, PhD
Phaik-Eng Sum is principal research scientist and discovery team leader at Wyeth Research. She was the principal research scientist in the project that discovered a new generation of broad spectrum potent tetracycline antibiotics, glycylcyclines, which showed potent activity against resistant bacteria. She has designed and synthesized several series of glycyclcycline prodrugs, one of which, Tigecycline was approved by the FDA on Jun 15, 2005.
Sum earned her PhD in organic chemistry at the University of British Columbia. She has held positions as a research associate at Wayne State University and the University of Rochester, and worked as a research chemist at American Cyanimid Company before joining Wyeth.
Patricia Bradford, PhD
Patricia Bradford is an associate director in infectious disease research at Wyeth Research in Pearl River, NY. She has worked on a number of antibiotic projects and was instrumental in the team that wrote the dossier for the registration of tigecycline. At Wyeth, she is currently the biology team leader for the β-lactamase Inhibitor Discovery Team and is the discovery co-chair of the Strategic Leadership Team for Infectious Diseases.
Bradford has over 50 publications in peer-reviewed scientific journals and has written several review articles and book chapters. She has been an editor for Antimicrobial Agents Chemotherapy since 2001 and serves as a reviewer for a number of other peer-reviewed journals and NIH grant review panels. She is also an advisor for the subcommittee on antimicrobial susceptibility testing of the Clinical Laboratory Standards Institute.
Prior to joining Wyeth, Bradford worked as a clinical microbiologist at Nebraska Methodist Hospital in Omaha. She received a PhD in medical microbiology from Creighton University.
Marilynn Larkin is a medical editor, journalist, and videographer based in New York City. Her work has frequently appeared in, among others, The Lancet, The Lancet Infectious Diseases, and Reuters Health's professional newswire. She has served as editor of many clinical publications and is author of five medical books for general readers as well as Reporting on Health Risk, a handbook for journalists. She is currently head of publications for The Society for Biomolecular Screening,
In 2004, Ms. Larkin started her own fitness consulting company (www.mlarkinfitness.com), and developed a class, Posture-cize, that helps people improve their posture, increase productivity, and reduce injury.