[Federal Register Volume 75, Number 248 (Tuesday, December 28, 2010)]
[Notices]
[Pages 81628-81630]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-32671]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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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: 301/496-7057; fax: 301/402-0220. 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:

[[Page 81629]]

     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; [email protected].
     John Stansberry, Ph.D.; 301-435-5236; 
[email protected].
    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 [email protected] 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

[[Page 81630]]

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; 
[email protected].

    Dated: December 21, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 2010-32671 Filed 12-27-10; 8:45 am]
BILLING CODE 4140-01-P