Drug – bio-affecting and body treating compositions – Miscellaneous
Reexamination Certificate
1998-11-13
2001-06-26
Prouty, Rebecca E. (Department: 1652)
Drug, bio-affecting and body treating compositions
Miscellaneous
C435S032000, C514S019300, C514S050000, C424S600000
Reexamination Certificate
active
06251955
ABSTRACT:
BACKGROUND OF THE INVENTION
Fungi are ubiquitous pathogenic organisms which can cause opportunistic infections in humans and other mammals. Some of these infections, although generally not life threatening, are widespread among the general population, occurring in one of the more common examples. In recent years, there has been an increase in infections caused by Candida and other fungal pathogens, especially those which have serious and even life threatening health implications. Such infections generally occur in patients with compromised immune systems, such as patients undergoing chemotherapy or corticosteroid treatments. This recent rise in life threatening fungal infections is largely a result of an increase in the number of transplants and the accompanying immunosuppressive therapies and of the spread of AIDS.
Unfortunately, there are few drugs available today for the treatment of fungal infections. Those that are available have serious shortcomings. They have a limited spectrum of activity, and many are toxic or are no longer effective because the target organism has become resistant. For example, pulmonary and disseminated infections caused by
Aspergillus fumigatus
in neutropenic or immunosuppressed patients are often fatal because treatments, such as the administration of Amphotericin B, are ineffective. Amphotericin B is also used for infections caused by Candida species,
Cryptococcus neoformans, Blastomyces dermatidis, Coccodioides immitis
, and
Histoplasma capsultatum
and has many undesirable side effects. Azoles, a class of anti-fungal agents (e.g. Fluconazole, used against Candida and
Cryptococcus nerformans
infections) can be effective, but are active against a limited range of fungi and resistant strains have emerged.
Pneumocystis carinii
is responsible for the most common opportunistic infection (pneumocystis pneumonia) in AIDS patients, in whom the infection is often fatal. Treatment with drugs such as trimethoprim-sulfamethoxazole and dapsone is often ineffective and may be limited by the drugs' toxicity.
Consequently, there exists a need for developing new therapies for treating infections by fungal pathogens. As an aid in developing new therapies, it would be of great value to have an assay which could rapidly detect new compounds which can interrupt a cellular process essential for growth or virulence of the fungi, and, thus, act as antifungal agents.
SUMMARY OF THE INVENTION
The present invention relates to a method of identifying inhibitors of fungal pathogenicity. These inhibitors may be fungistatic or fungicidal. This assay is based on the discovery that fungal pathogenicity is dependent on the levels of chitin in the cell wall and that pathogenicity can therefore be reduced or removed through the inhibition of chitin synthase III. In one embodiment of the method of the present invention, a mutant strain of fungus containing a mutated chitin synthase II gene is cultured in the presence of a molecule or compound to be assessed for its ability to inhibit chitin synthase III. If the molecule or compound is a chitin synthase III inhibitor, the mutant strain will show diminished growth when compared to the growth of wild type strain of fungus cultured under the same conditions in the presence of the molecule or compound. In a second embodiment of the present method, a first strain and a second strain of a fungus are cultured in the presence of a compound or molecule to be assessed for its activity as a chitin synthase III inhibitor. The first strain contains an inhibited chitin synthase II and shows diminished growth in the presence of a chitin synthase III inhibitor, compared to the growth of the second strain of fungus, which does not contain inhibited chitin synthase II, cultured under the same conditions in the presence of the molecule or compound.
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Hamilton Brook Smith & Reynolds P.C.
Millennium Pharmaceuticals Inc.
Prouty Rebecca E.
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