Accelerator Funded Projects Available for Licensing
Development of Broad Spectrum Antibiotics for New Targets
Download the Opportunity Statement here.
Case Numbers: HU 2987, 2985, 2831, 2704
Principal Investigators:
Daniel Kahne, Ph.D.
Professor of Chemistry and Chemical Biology, Harvard University
Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Suzanne Walker, Ph.D.
Professor of Microbiology and Molecular Genetics, Harvard Medical School
Executive Summary
In light of the public health threat posed by antibiotic resistance, scientists at Harvard University led by Profs. Daniel Kahne and Suzanne Walker have launched a dedicated program aimed at elucidating the essential processes in bacterial cell envelope biogenesis and developing a new generation of novel, broad spectrum antibiotics to treat multi-drug resistant bacterial infections.
The laboratories of Kahne and Walker have developed an approach that integrates chemistry and biology to develop new and effective antibiotics. Peptidoglycan glycosyltransferases (PGTs) are a family of bacterial enzymes involved in the biosynthesis of the peptidoglycan matrix of the bacterial cell wall. PGTs are promising targets for antibiotics because they are essential for bacteria but have no eukaryotic homologs. Therefore, antibiotics against PGTs will likely to be highly specific against infections and are expected to show good safety profiles. Also, PGTs are located on the external surface of the cytoplasmic membrane where they are readily accessible to small molecule inhibitors.
Moenomycin, a potent natural product that binds to the active site of PGTs, is the only known inhibitor of peptidoglycan glycosyltransferases. On a molar basis, moenomycin A is a thousand times more potent than vancomycin. However, the therapeutic utility of moenomycin is limited by its poor pharmacokinetic properties, including an excessively long half-life and minimal oral bioavailability. In addition, although moenomycin strongly inhibits Gram-negative PGTs, its spectrum is restricted to Gram-positive microorganisms. The Kahne/Walker group has determined to overcome these limitations by redesigning moenomycin into a broad-spectrum antibiotic suitable for clinical use. Like many other natural products, the chemical structure of moenomycin is so complex that developing new synthetic routes for novel derivatives requires considerable expertise and know-how. The Kahne/Walker group, with its strong background in both synthetic chemistry and molecular biology, is well positioned competitively to develop and synthesize novel analogs of moenomycin and to evaluate their potential for further development as antibiotics. Currently, scientists in the Kahne/Walker group are working towards key goals including (1) optimizing serum half-life of moenomycin; (2) broadening the antibacterial spectrum to include significant Gram negative pathogens; and (3) defining the frequency and molecular mechanisms for drug resistance. Taken together, the cumulative know-how and technological tools developed by the Kahne lab will provide the basis for potential breakthroughs in the development of new antibiotics to treat multi-drug-resistant bacterial infections, and also a solid foundation upon which to build a new therapeutics business or franchise, as appropriate.
Market Opportunity
In American hospitals alone, healthcare-associated infections account for an estimated 1.7 million infections and 99,000 associated deaths each year. According to the Centers for Disease Control, 5 to 10% of patients admitted to the hospital have or develop an infection, and 70% of the bacteria causing these infections are resistant to at least one of the antimicrobial agents approved for human use. In 2006, antibiotics are generating sales approaching $20B in the major pharmaceutical markets.
The Kahne/Walker group: Highlights of Accomplishments
Over 30 years, prominent synthetic chemists have studied possible synthetic routes towards moenomycin without success. The key difficulty is that some of the five sugar rings making up moenomycin carry functional groups which are highly sensitive to the chemical conditions commonly used to link sugars together. In addition, poor pharmacokinetic properties related to the C25 isoprenoid chain of natural moenomycin have prevented its use in humans. In recent years, researchers in the Kahne lab achieved significant scientific progress that overcomes these barriers by developing: (1) a novel degradation/ reconstruction route to manipulate the reducing end of moenomycin A, allowing the preparation of active moenomycin analogues with shorter lipid chains suitable for human use; and (2) the first reported total synthesis of moenomycin A.
In collaboration with Prof. Suzanne Walker at Harvard Medical School, the Kahne and the Walker labs have developed a number of tools to exploit the potential of moenomycin. For instance, they have developed new methods to alter the structure of moenomycin—most significantly, the completion of the aforementioned total synthesis of moenomycin by the Kahne laboratory and the discovery of the moenomycin biosynthetic genes in Streptomyces ghanaensis by the Walker laboratory. The combination of synthetic chemistry to make moenomycin analogs and enzymatic reactions to facilitate the production of intermediates makes it possible to explore a range of analogs rapidly by semi-synthetic routes. In addition, the labs have jointly solved the crystal structure of a PGT-moenomycin analog complex. The resulting data are providing important structure-activity relationship information for the design of novel moenomycin analogs. Furthermore, a crystal soaking method has been established to obtain other co-complexes rapidly, which will enable iterative improvements in analog design. Finally, the labs possess a panel of purified PGTs from different organisms and have developed a range of in vitro assays to study the mechanism of action of potential hits. Together, these powerful tools and fundamental scientific discoveries will be used as the basis for medicinal chemists to further improve moenomycin as a potent and novel antibiotic to treat infectious diseases.
Resources
Kahne/Walker group research is centered in their labs in Harvard University Department of Chemistry and Chemical Biology and Harvard Medical School Department of Microbiology and Molecular Genetics. The group is presently scaling up, expanding and recruiting new FTEs, including three postdoctoral fellows (two synthetic chemists and one microbiologist). Overall, the Kahne moenomycin group presently comprises 5 individuals, with the long term goal of doubling in size.
Partnership Opportunity and Value Proposition
The Kahne/Walker moenomycin program is, as yet, uncommitted to industry. Harvard seeks a long-term alliance with a company offering franchise-leading competencies in infectious disease and antibiotics development. A long-term relationship is sought with the company best able to demonstrate its capabilities and commitment to the area. Partnership will be aimed at developing novel therapeutics, and will couple commercial development of Harvard IP together with long term support of ongoing research on a program-wide scale, including mechanistic and characterization studies, as well as hit-to-lead screening activities, in the Kahne and Walker labs. Harvard’s first mover advantage (particularly in the biological and synthetic routes) provides proprietary composition of matter and the researchers' deep knowledge of the biological target and pathways will provide leading expertise in this domain.
Intellectual Property
Harvard University believes in vigorous protection of its intellectual property. Multiple patent applications have been filed covering processes to prepare derivatives, compound use claims, and novel compositions of matter.
Selected Publications:
- Adachi M, Zhang Y, Leimkuhler C, Sun B, LaTour JV, Kahne DE. 2006. Degradation and Reconstruction of Moenomycin A and Derivatives: Dissecting the Function of the Isoprenoid Chain. J. AM. CHEM. SOC. 128:14012-14013. This publication is available in Adobe PDF.
- Taylor JG, Li X, Oberthür M, Zhu W, Kahne DE. 2006. The Total Synthesis of Moenomycin. J. AM. CHEM. SOC. 128:15084-15085. This publication is available in Adobe PDF.
- Yuan Y, Fuse S, Ostash B, Sliz P, Kahne D, Walker S. 2008. Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design. ACS Chem Biol. 3(7):429-36. This publication is available in Adobe PDF.
- Yuan Y, Barrett D, Zhang Y, Kahne D, Sliz P, Walker S. 2007. Crystal structure of a peptidoglycan glycosyltransferase suggests a model for processive glycan chain synthesis. Proc Natl Acad Sci U S A. 104(13):5348-53. This publication is available in Adobe PDF.
- Ostash B, Doud EH, Lin C, Ostash I, Perlstein D, Fuse S, Wolpert M, Kahne D, Walker S. 2009. Complete characterization of the seventeen step moenomycin biosynthetic pathway. Biochemistry. Jul 29, 2009.[Epub ahead of print]. This publication is available in Adobe PDF.
For additional information, contact:
Laura Brass, Ph.D.
Director of Business Development
Office of Technology Development
Harvard University
By phone: (617) 495-3067
By email: laura_brass@harvard.edu