Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for...
Reexamination Certificate
1997-06-16
2001-01-16
Hobbs, Lisa J. (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
C435S006120, C435S252300, C435S254110, C435S325000, C435S320100, C536S023200, C536S024300
Reexamination Certificate
active
06174713
ABSTRACT:
BACKGROUND OF THE INVENTION
Candida albicans
is an opportunistic pathogen and the most common fungus causing systemic infections in man including both bloodstream infections in hospitalized immunocompromised patients and vaginal infections (for review, see: Mandell, G. L.; Bennett, J. E.; and Dolin, R. (Eds),
Principles and Practice of Infectious Disease,
4th ed., Churchill Livingston: New York, 1995; Vol 2, Chapter 237). The increasing use of immunosuppressive therapy for malignancy and transplantation, the increase in intensive care patients receiving broad spectrum antibiotic therapy, and the AIDS epidemic have greatly increased the number of patients susceptible to opportunistic infections caused by
C. albicans.
In particular, infections due to Candida increased by almost 500% over the decade of the 1980s and continue to rise in the 1990s, becoming the fourth most common blood-stream pathogen (see: Pfaller, M. A.
Journal of Hospital Infection
30 suppl. 329-38 1995). It has been reported that 90% of AIDS patients have some type of Candida infection.
C. albicans
can invade the kidneys, heart, liver, lungs, spleen, brain and eyes. These infections are difficult to detect and can lead to death.
A limited number of antifungal agents are available for the treatment for
C. albicans
infections. Amphotericin B, the mainstay of antifungal therapy, has limited clinical utility in treating Candida infection due to its associated toxicities and requirement for intravenous administration. Flucytosine too is limited due to its bone marrow toxicity and to the appearance of resistance. The azole antifungal agents have become the first choice of therapy for Candida infection and fluconazole is the most frequent drug prescribed in the 1990's. However, reports of resistance to these azole antifungals have appeared in recent years (see: Dupont, B.
Current Opinion in Infectious Diseases
8, 424-427 1995). Because of the development of resistance to antifungals and adverse side-effects of current therapies for Candida infection, there is continuing need for new drug targets and new antibiotics.
SUMMARY OF THE INVENTION
The invention relates to isolated and/or recombinant nucleic acids which encode cytoplasmic tryptophanyl-tRNA synthetases of Candida origin. The invention also relates to recombinant DNA constructs and vectors containing DNA having a sequence which encodes a cytoplasmic tryptophanyl-tRNA synthetase of Candida origin or portions of the enzyme. These nucleic acids and constructs can be used to produce recombinant cytoplasmic tryptophanyl-tRNA synthetases of Candida origin.
A further embodiment of the invention is antisense nucleic acid which can hybridize to the nucleic acid which encodes a cytoplasmic tryptophanyl-tRNA synthetase of Candida. In cells, antisense nucleic acid can inhibit the function of an RNA which encodes a cytoplasmic tryptophanyl-tRNA synthetase of Candida.
The invention also relates to proteins or polypeptides, including fusion proteins, referred to herein as isolated and/or recombinant Candida cytoplasmic tryptophanyl-tRNA synthetases. These proteins are useful in the synthesis of peptides and related products; in assays to identify inhibitors of cytoplasmic tryptophanyl-tRNA synthetase function (including inhibitors having antimicrobial activity); in biochemical separations of tryptophan; and in quantitations of tryptophan and ATP. Antibodies which bind to cytoplasmic tryptophanyl-tRNA synthetases can be made and can be used in the purification and study of these enzymes.
Recombinant Candida cytoplasmic tryptophanyl-tRNA synthetases can be produced in host cells using cells and methods described herein. Tester strains, which are cells engineered to rely on the function of the tRNA synthetase encoded by an introduced cloned gene, are also an embodiment of the invention. Tester strains can be used to test the effectiveness and/or specificity of drug candidates in the inhibition of the essential tRNA synthetase enzyme encoded by the introduced cloned gene. In this way, potential inhibitors of the enzyme can be screened for antimicrobial or antibiotic effects, without requiring the culture of pathogenic strains of Candida, such as
Candida albicans.
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Houman Fariba
Shen Xiaoyu
Cubist Pharmaceuticals, Inc.
Hamilton Brook Smith & Reynolds P.C.
Hobbs Lisa J.
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