[Federal Register Volume 75, Number 122 (Friday, June 25, 2010)]
[Notices]
[Pages 36423-36424]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-15476]
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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 Invention: 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 sittings.
Since FtsZ is structurally similar, but do 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:
[[Page 36424]]
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 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, PhD, MBA; 301-435-4616;
[email protected]; or John Stansberry, PhD; 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.
Hepatoma Cell Line That Can Be Infected With Both Hepatitis C and Human
Immunodeficiency (HIV-1) Viruses
Description of Invention: It is estimated that 250,000 HIV patients
in the U.S. are chronically infected with hepatitis C virus (HCV). Co-
infection of HCV and HIV is associated with increased morbidity and
mortality relative to mono-infection with either virus. Compared to HCV
mono-infected individuals, HCV/HIV co-infected individuals experience
rapid progression of liver disease, have higher HCV RNA viral levels,
decreased cure rates, and increased toxic reactions to anti-HCV
therapy. Understanding how these two viruses interact has been
difficult because a cell culture system that supports HCV growth in the
laboratory was not available. Recently, a continuous culture system to
propagate HCV was discovered, however these cells do not express
receptors that allow for infection by HIV. The inventors were able to
genetically transform these cells (liver cancer) to express HIV
receptors and successfully infect them with both viruses. This modified
cell culture system will be useful for studying the interactions
between HCV and HIV within the same cell and will serve as a model to
understand the pathogenesis of HCV/HIV co-infection.
Applications:
Use for clinical research to study the pathogenesis of
HCV/HIV co-infection.
Use in development of drugs to control both HIV and HCV
infections.
Development Status:
The cell line has been fully generated.
Materials will be readily available if so requested.
Inventors: Shyam Kottilil, Xiaozhen Zhang, and Marybeth E. Daucher
(NIAID).
Relevant Publication: Matthews GV and Dore GJ. HIV and hepatitis C
coinfection. J Gastroenterol Hepatol. 2008 Jul;23(7 Pt 1):1000-1008.
[PubMed: 18707597].
Patent Status: HHS Reference No. E-107-2009/0--Research Material.
Patent protection is not being pursued for this technology.
Licensing Status: Available for licensing.
Licensing Contacts: Uri Reichman, PhD, MBA; 301-435-4616;
[email protected]; or John Stansberry, PhD; 301-435-5236; [email protected].
Dated: June 21, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of
Technology Transfer, National Institutes of Health.
[FR Doc. 2010-15476 Filed 6-24-10; 8:45 am]
BILLING CODE 4140-01-P