[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]
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