Histidine kinases of Aspergillus and other fungal species,...

Details Histidine kinases of Aspergillus and other fungal species,... Histidine kinases of Aspergillus and other fungal species,...

2000-08-09

2004-04-06

Hutson, Richard (Department: 1652)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S194000, C435S183000, C435S252100, C435S252300, C435S320100, C435S410000, C435S091500, C435S023000, C435S023000, C435S023000, C435S091500, C435S350000

Reexamination Certificate

active

06716625

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to fungal histidine kinases. In particular, the present invention is directed to histidine kinases from Neurospora (e.g.,
N. crassa
), Candida (e.g,
C. albicans
), and Aspergillus (e.g.,
A. fumigatus
), and related compositions. Furthermore, the present invention provides compositions and methods for the identification of compounds having antifungal activity, as well as compositions and methods for the treatment of fungal infections.
BACKGROUND
Fungal organisms have become increasingly significant pathogens in immunocompromised patients, especially those who because of cancer, organ transplantation, chemotherapy, pregnancy, age, diabetes, complications following extensive surgery, and various immune system dysfunctions, are at risk of experiencing life-threatening diseases caused by organisms which do not ordinarily pose a threat to normal, immunocompetent people. Indeed, immunocompromised patients perhaps provide the greatest challenge to modern health care delivery. For example, fungal infections have become one of the leading factors contributing to morbidity and mortality in cancer patients, and fungi account for 4-12% of nosocomial (hospital-acquired) pathogens in leukemia patients (E. Anaissie, Clin. Infect. Dis., 14[Suppl.1]:S43 [1992]). The incidence of nosocomial bloodstream infections with fungi such as Candida (“candidemia”) has increased in recent years and now accounts for 5.6% of all primary bloodstream infections (Id.). There are an estimated 200,000 patients/year who acquire nosocomial fungal infections, with bloodstream infections having a mean mortality rate of 55% (See e.g., Beck-Sague et al., J. Infect. Dis., 167:1247 [1993]; and the Centers for Disease Control website at www.cdc.gov
cidod/publications/brochures/hip.html). Fungi infections may also be life-threatening in other settings, such as in the case of intravenous drug abusers who use non-sterile substances to dilute drugs prior to injection.
Deep-seated mycoses are being increasingly observed in patients undergoing organ transplants and aggressive chemotherapy. For solid organ transplantation, the incidence of fungal infections ranges from 5% in kidney recipients, 15-25% in lung and heart recipients, and up to 40% in liver recipients (Alexander et al., Drugs 54:657 [1997]). The most common fungal pathogens are the opportunistic yeast,
C. albicans
and the filamentous mold,
A. fumigatus
(See, Bow, Br. J. Haematol., 101:1 [1998]; and Warnock, J. Antimicrob. Chemother., 41:95 [1998]).
AIDS patients are also at great risk for fungal infections. An estimated 80% of AIDS patients acquire fungal infections and suffer a mortality rate of 10-20% as a result of these infections (See, Cairns, J. Electron Microsc. Techn. 8:115 [1988]).
Candida
Of the over 100 Candida species, approximately seven are isolated with great frequency from human specimens (T. Mitchell, in
Zinsser Microbiology
, W. K. Joklik, et al., [eds], Appleton, Century-Crofts, Norwalk, Conn., pp. 1183-1190 [1984]). A brief taxonomic chart of Candida is shown in Table 1. Some Candida species are related to organisms, such as Saccharomyces in the subclass Hemiascomycetidae, class Ascomycetes, subdivision Ascomycotina, division Ascomycota. Also, some mycologists consider
C. stellatoidea
to be a variant of
C. albicans.
TABLE 1
TAXONOMY OF THE GENUS CANDIDA
Kingdom:
Mycetae (Fungi)
Division:
Deuteromycota
Subdivision:
Deuteromycotina
Form Class:
Deuteromyces
Form Subclass:
Blastomycetidae
Genus:
Candida
Species:
albicans
glabrata
guilliermondi
krusei
lipolytica
lusitaniae
parapsilosis
pseudotropicalis
rugosa
stellatoidea
tropicalis
The first exposure to fungi experienced by many humans occurs during the birth process, when
C. albicans
present in the mother's vaginal canal colonizes the buccal cavity, and portions of the upper and lower gastrointestinal tract of the newborn. This colonization usually results in the establishment of
C. albicans
as a commensal organism in these areas, for the life of the individual. However,
C. albicans
is also the most common fungal pathogen of humans, worldwide, with other Candida species becoming increasingly important in fungal disease in humans and other animals.
As a commensal,
C. albicans
exists as a unicellular yeast; during invasive disease, the organism has a filamentous morphology. The implication of
C. albicans
in disease may indicate that the patient has a co-existing immune, endocrine or other debilitating disorder that must also be addressed in order to effectively manage the fungal disease. The principal risk factors that predispose individuals to deeply invasive candidiasis include protracted course of broad spectrum antimicrobials, cytotoxic chemotherapy, corticosteroids, and vascular catheters.
Candida Infection and Diagnosis
Because clinical Candida infections and disease may be acute or chronic, superficial or disseminated, the disease syndromes are many and varied. While
C. albicans
is most commonly implicated, various other Candida species can and do invade most organ systems of the body. For example,
C. tropicalis, C. parapsilosis, C. guilliermondi, C. krusei
, and
C. lusitaniae
have emerged as important pathogens in cancer patients (E. Anaissie, supra). Candidiasis due to
C. albicans
, as well as other Candida species, is the most common opportunistic fungal infection observed (See, Walsh and Dixon, “Spectrum of Mycoses,” in Baron (ed.),
Medical Microbiology
, 4th ed, University of Texas Medical Branch, Galveston, Tex. [1996], pp. 919-925). Superficial candidiasis may involve the epidermal and mucosal surfaces (e.g., the oral cavity, pharynx, esophagus, intestines, urinary bladder, and vagina). In deep candidiasis, the gastrointestinal tract and intravascular catheters are the two major portals of entry, with the kidneys, liver, spleen, brain, eyes, heart, and other tissues being the major sites involved.
The major difficulties in treating Candida infections are encountered in cases of systemic disease. Chronic mucocutaneous, pulmonary candidiasis, endocarditis, and fungemia must be diagnosed early and treated promptly with an appropriate antifungal regimen, in order to avoid fatality (W. Chandler,
Color Atlas and Text of Histopathology of Mycotic Diseases
, p. 44 [1980]). The incidence of candidiasis in certain patient populations is striking. Up to 30% of leukemia patients acquire systemic candidiasis (E. Anaissie, supra). This is of great significance, as some reports indicate that the fatality rate for disseminated candidiasis in cancer patients is 80% (F. Meunier, et al., Clin. Infect. Dis., 14[Suppl. 1]:S120 [1992]). Also, fatalities in most organ transplant patients who succumb to infection are most often due to opportunistic organisms, of which Candida is the leading mycotic agent (T. Mitchell, supra).
The probability of postoperative systemic candidiasis is related to the length of operation and may involve contamination with organisms during the surgery or contamination through such diverse postoperative procedures as indwelling catheters or the use of prophylactic antibacterial compounds (Id.). Prosthetic devices, including artificial heart valves or intravenous lines can be colonized and introduce Candida into the patient's bloodstream (Id.).
Significantly, many patients who develop systemic candidiasis were given corticosteroids prior to development of their Candida infection. Corticosteroids are known to depress the immune system and are often used to prevent transplant rejection. Corticosteroids and antibacterials predispose to candidiasis by depressing phagocytic activity and cell-mediated immunity, reducing the bacterial flora and indirectly increasing the Candida population (Id.). Perhaps also importantly, corticosteroids have been hypothesized to directly act on fungi and may contribute to disease progression in patients with systemic candidiasis (See e.g.,

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