2010-32671. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, HHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: [phone]; fax: [phone]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

A New Class of Antibiotics: Natural Inhibitors of Bacterial Cytoskeletal Protein FtsZ to Fight Drug-susceptible and Multi-drug Resistant Bacteria

Description of Technology: The risk of infectious diseases epidemic has been alarming in recent decades. This is not only because of the increase incident of so-called “super bugs,” but also because of the scarce number of potential antibiotics in the pipeline. Currently, the need for new antibiotics is greater than ever! The present invention by the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), part of the National Institute of Health (NIH), address this urgent need. The invention is a new class of chrysophaentin antibiotics that inhibit the growth of broad-spectrum, drug-susceptible, and drug-resistant bacteria.

Derived from the yellow algae Chrysophaeum taylori, the inventor has extracted 8 small molecules of natural products and tested for antimicrobial activity against drug resistant bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), as well as other drug susceptible strains. Structurally, the molecules represent a new class of antibiotic that also likely work through a distinct mechanism of action from that of current antibiotics, which is key for the further development of antibiotics that inhibit drug-resistant strains.

The bacterial cytoskeletal protein FtsZ is a GTPase and has structural homology to the eukaryotic cytoskeletal protein tubulin, but lacks significant sequence similarity. FtsZ is essential for bacterial cell division. It is responsible for Z-ring assembly in bacteria, which leads to bacterial cell division. Experiments show that the disclosed compounds are competitive inhibitors of GTP binding to FtsZ, and must bind in the GTP-binding site of FtsZ. Inhibition of FtsZ stops bacterial cell division and is a validated target for new antimicrobials. FtsZ is highly conserved among all bacteria, making it a very attractive antimicrobial target.

Applications:

• Therapeutic potential for curing bacterial infections in vivo, including for clinical and veterinary applications.
• Antiseptics in hospital settings.
• Since FtsZ is structurally similar, but does not share sequence homology to eukaryotic cytoskeletal protein tubulin, these compounds may have antitumor properties against some cancer types or cell lines.

Advantages:

• Structurally distinct antimicrobial compounds.
• Attack newly validated antibacterial targeted protein FtsZ.
• These compounds have a unique mechanism of action which inhibit FtsZ by inhibiting FtsZ GTPase activity.
• Inhibit drug-susceptible and drug-resistant bacteria.

Development Status:

• Initial isolation and chemical structural characterization using NMR spectroscopy have been conducted.
• Antimicrobial testing against MRSA, Enterrococcus faecium, and VRE were conducted in vitro using a modified disk diffusion assay and microbroth liquid dilution assays.
• MIC₅₀ values were determined using a microbroth dilution assay.
• Mode of action was elucidated and Saturation Transfer Difference (STD) NMR was conducted to map the binding epitope of one of these compounds in complex with recombinant FtsZ.
• Other experiments on different areas to further characterize these compounds and their mode of action are currently ongoing.

Market: The market potential for the disclosed compounds is huge due to the very limited number of new antibiotics developed in recent decades and the increased epidemic of infectious diseases. In fact, infectious diseases are the leading cause of death worldwide. In the United States alone, more people die from MRSA than from HIV (Journal of the American Medical Association, 2007) and more than 90,000 people die each year from hospital acquired bacterial infections (Centers for Disease Control).

According to the recent report, “Antibiotics Resistance and Antibiotic Technologies: Global Markets ” published in November 2009, there has been a revival in the antibiotics sector over the past few years. Although some companies are developing analogues of existing antibiotic classes and putting them into clinical trials, other start-up biotechnology companies have come up with molecules that adopt new approaches in tackling antimicrobial infections. The antibacterials market can be split into two major groups: The community market and the hospital market. The smaller hospital market is expanding more rapidly, driven by rising resistant rates, a more severely ill patient population and newer, premium-priced injectable antibiotics. Interestingly, several big pharmaceutical companies have recently made strategic decisions to expand their presence in this sector by either acquiring other companies or in-licensing new compounds.

While the number of such new molecules in the approval stages is still low, R&D pipelines are promising, and several novel classes of antibiotics are in their early stages of development. This antibacterial R&D bailout that started about 5 years ago due to tougher regulatory conditions, restrictions on the use of antibiotics and emergence of resistance to newer antibiotics within 3 years has helped create a global antimicrobial therapeutic market of $24 billion in 2008 with 14 products recording sales of more than $1 billion.

Inventors: Carole A. Bewley et al. (NIDDK).

Related Publications:

1. DJ Haydon et al . An inhibitor of FtsZ with potent and selective anti-staphylococcal activity. Science. 2008 Sept 19; 321(5896):1673-1675. [PubMed: 18801997].

2. NR Stokes et al. Novel inhibitors of bacterial cytokinesis identified by a cell-based antibiotic screening assay. J Biol Chem. 2005 Dec 2; 280(48):39709-39715. [PubMed: 16174771].

3. J Wang et al. Discovery of small molecule that inhibits cell division by blocking FtsZ, a novel therapeutic target of antibiotics. J Biol Chem. 2003 Nov 7; 278(45):44424-44428. [PubMed: 12952956].

4. P Domadia et al. Berberine targets assembly of Escherichia coli cell division protein FtsZ. Biochemistry. 2008 Mar 11; 47(10):3225-3234. [PubMed: 18275156].

5. P Domadia et al . Inhibition of bacterial cell division protein FtsZ by cinamaldehyde. Biochem Pharmacol. 2007 Sep 15:74(6):831-840. [PubMed: 17662960].

6. S Urgaonkar et al. Synthesis of antimicrobial natural products targeting FtsZ: (+/-)-dichamanetin and (+/-)-2′″-hydroxy-5″-benzylisouvarinol-B. Org Lett. 2005 Dec 8;7(25):5609-5612. [PubMed: 16321003].

Patent Status: U.S. Provisional Application No. 61/308,911 filed 27 Feb 2010 (HHS Reference No. E-116-2010/0-US-01).

Licensing Status: Available for licensing.

Licensing Contacts:

• Uri Reichman, Ph.D., MBA; 301-435-4616; [e-mail].
• John Stansberry, Ph.D.; 301-435-5236; [e-mail].

Collaborative Research Opportunity: The National Institute of Diabetes and Digestive and Kidney Diseases, Laboratory of Bioorganic Chemistry is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the chrysophaentin antibiotics. Please contact Cindy K. Fuchs at 301-451-3636 or [e-mail] for more information.

GATA-3 Reporter Plasmids for Revealing Underlying Mechanisms in Breast Cancer

Description of Technology: Scientists at the National Institutes of Health (NIH) have developed GATA-3 gene reporter plasmids that express a green fluorescent protein (GFP) or luciferase reporter protein under the control of a GATA-3 promoter. Cells expressing this plasmid will glow fluorescent green or emit light energy, respectively, if GATA-3 gene expression is activated in the cells. The reporter construct allows cells where GATA-3 gene expression is activated to be isolated and collected for further analysis or be monitored in the host environment.

GATA-3 is a transcription factor that is highly expressed in several types of cells and is a critical transcription factor for the development of particular lineages of hematopoietic cells and normal mammary luminal epithelium. GATA-3 plays a regulatory role in determining the fate of cells in the hematopoietic systems and the mammary gland. Disruption of GATA-3 expression leads to defects in the development of sub-types of lymphoid cells and luminal mammary epithelial cells. GATA-3 expression is highly associated with luminal sub-types of breast cancer, whereas expression of GATA-3 is low or undetectable in basal subtypes of breast cancer which often have a poor prognosis. Low or limited GATA-3 expression is correlated with larger tumors, increased likelihood of tumor-positive lymph nodes, and predicts an overall poorer clinical outcome compared to patients with higher mammary GATA-3 expression. Researchers believe that a better understanding of GATA-3 function and its dysregulation during the onset and progression of breast cancer will lead to new strategies in diagnosing and treating the disease.

Applications:

• Research tool to help identify factors that modify GATA-3 expression that may serve as potential therapeutic targets for developing drugs to treat breast cancer or hematologic malignancies.
• Research tool that could be utilized as an important component of a breast cancer diagnostic kit or platform to better understand the most effective treatment options for individual breast cancer patients.
• Molecular tool to better understand the mechanisms that contribute to hematopoietic and mammary cell/gland development and differentiation in order to identify the critical stages where dysfunction can lead to the onset of breast cancer.
• Molecular biology laboratory tool for sorting breast cancer positive and negative cells so that further comparative experiments can be performed to understand the cellular properties of the two sets of cells.

Advantages:

• Useful for in vitro and in vivo assays: Using the GFP or luciferase expression of these reporter plasmids, researchers can identify cells expressing various levels of GATA-3 and isolate these different subsets in vitro. These reporter constructs can also be transfected into cells to measure GATA-3 expression levels in vivo in real time from hematopoietic and breast cancer models.
• Possible identification of new targets for breast cancer therapy: The reporter plasmids could be utilized to identify factors that serve to activate GATA-3 in normal mammary cells or inhibit GATA-3 expression in breast cancer cells. Such factors could serve as targets for novel breast cancer therapies.

Inventors: Hosein Kouros-Mehr (formerly NCI) and Jeffrey E. Green (NCI)

Selected Publications:

1. H. Kouros-Mehr, et al. GATA-3 and the regulation of the mammary luminal cell fate. Curr Opin Cell Biol. 2008 Apr;20(2):164-170. [PubMed: 18358709]

2. H. Kouros-Mehr, et al. GATA-3 links tumor differentiation and dissemination in the luminal breast cancer model. Cancer Cell 2008 Feb;13(2):141-152. [PubMed: 18242514]

3. H. Kouros-Mehr, et al. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 2006 Dec 1;127(5):1041-1055. [PubMed: 17129787]

Patent Status: HHS Reference No. E-128-2009/0—Research Tool. Patent protection is not being pursued for this technology.

Licensing Status: Available for licensing under a Biological Materials License Agreement.

Licensing Contact: Samuel E. Bish, Ph.D.; 301-435-5282; [e-mail].

Dated: December 21, 2010.

Richard U. Rodriguez,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.