[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