Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-03-09
2004-03-16
Swartz, Rodney P (Department: 1645)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C435S183000, C435S091100, C435S254220, C536S023200, C530S333000, C424S054000
Reexamination Certificate
active
06706688
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methodologies and molecular targets for the prevention and treatment of microbial infection of a mammalian host through the disruption of the
Candida albicans
homologue of adenylate cyclase-associated protein (CAP1) gene. Preferably, these methods and molecular targets may be used in the prevention and treatment of microbial infection of mammalian hosts such as immunocompromised patients at risk for opportunistic fungal infections, organ transplant patients, cancer patients undergoing chemotherapy, burn patients, AIDS patients, or patients with diabetic ketoacidosis.
BACKGROUND OF THE INVENTION
Whether pathogenic or opportunistic, microorganisms have evolved numerous mechanisms to facilitate their establishment and proliferation in mammalian hosts. During initial infection, the interaction of a microorganism with its mammalian host can include attachment or adhesion to the host cell surface, and invasion of host cells, for example. In certain instances, this interaction can be nonspecific. In others, such microbial interaction involves the specific binding of the microorganism to a particular receptor or receptor complex expressed on the host cell surface. In turn, the binding event can trigger changes in the microorganism and/or the mammalian host cell, leading to the progression of infection.
Candida is an ubiquitous yeast recognized as the causative agent of candidiasis (
Candida mycosis
). At least 90% of the disorders are caused by the species
Candida albicans
, which is an opportunistic yeast that elicits only mild superficial infections in normal individuals. However, destabilization of the host-parasite equilibrium upon inopportune loss or deficiencies in protective innate and immune deterrents favors overgrowth of the common gastrointestinal tract denizen and opportunistic pathogen,
C. albicans
. Acquired immunodeficiency syndrome (AIDS) or iatragenic immunosuppression are risk factors for oropharyngeal and esophageal candidiasis (Hood et al., 28 Clin. Infect. Dis. 587-96 (1999)). Thus, oropharyngeal and esophageal candidiasis are among the most frequent opportunistic fungal infections observed in human immunodeficiency virus positive (HIV+) and AIDS patients, occurring in the majority of patients. Candidal infections increase in severity and recur more frequently as the immunodeficiency progresses. The current status of the AIDS epidemic is one of increasing numbers of individuals infected and no cure. Many infected individuals may live for a long time with HIV in an essentially permanent immunocompromised state. Because of the loss of the cellular component of the immune system, AIDS patients are susceptible to invasion of submucosal tissue by
C. albicans
. In addition to HIV infected patients, oral candidiasis occurs in patients with leukemia or other cancers, as well as in patients with other underlying diseases. Prematurely-born infants are also at risk and may acquire mucosal infections causing permanent sequelae (Huang et al., 30 Scand. J. Infect. Dis. 137-42 (1998); Sood et al., 41 MYCOSES 417-9 (1998)). Candidiasis in denture wearers, or denture stomatitis, is the most common of all
C. albicans
associated diseases.
Although
C. albicans
is sensitive to antifungal drugs, treatment over long periods of time are required. At present, the treatment for invasive infections is based on relatively few antimycotics. Nystatin, ketoconazole, and amphotericin B are drugs which are used to treat oral and systemic Candida infections. However, orally administered nystatin is limited to treatment within the gut and is not applicable to systemic treatment. Some systemic infections are susceptible to treatment with ketoconazole or amphotericin B, but these drugs may not be effective in such treatment unless combined with additional drugs. Amphotericin B has a relatively narrow therapeutic index and numerous undesirable side effects and toxicities occur even at therapeutic concentrations. While ketoconazole and other azole anti fungals exhibit significantly lower toxicity, their mechanism of action, inactivation of cytochrome P
450
prosthetic group in certain enzymes (some of which are found in humans), precludes use in patients that are simultaneously receiving other drugs that are metabolized by the body's cytochrome P
450
enzymes. See, e.g., U.S. Pat. No. 5,863,762.
Other known antifungal agents include: polyene derivatives, such as amphotericin B (including lipid or liposomal formulations thereof) and the structurally related compounds nystatin and pimaricin; flucytosine (5-fluorocytosine); azole derivatives (including ketoconazole, clotrimazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, tioconazole, terconazole, fluconazole, itraconazole, voriconazole [Pfizer] and SCH56592 [Schering-Plough]); allylamines-thiocarbamates (including tolnaftate, naftifine and terbinafine); griseofulvin; ciclopirox; haloprogin; echinocandins (including MK-0991 [Merck]); nikkomycins; and bactericidal/permeability-increasing protein (BPI), described in U.S. Pat. Nos. 5,627,153; 5,858,974; 5,652,332; 5,763,567; and 5,733,872. Unfortunately, antimycotics cause serious, sometimes different, side effects, such as renal insufficiency, hypocalcemia and anemia, as well as unpleasant constitutional symptoms such as fever, shivering and low blood pressure.
The frequency of candidal infections may be a result of the prophylactic use of antibacterial drugs used in AIDS patients to minimize other opportunistic infections. Emergence of drug-resistant isolates and the limited selection of antifungal drugs point to the need for research aimed at identifying new anti-fungal targets (Terrell, 74 Mayo Clin. Proc. 78-100 (1999)). However, the pathogenesis is complex and is thought to involve multiple host factors that include loss of cell mediated immunity and altered phagocytic cell activity. High frequencies of nosocomial candidemia reflect the ability of
C. albicans
to translocate across the gastrointestinal tract, disrupting internal tissues in debilitated patients (Viscoli et al., 28 Clin. Infect. Dis. 1071-9 (1999)).
Thus far, studies have shown that development of candidiasis is a multi-stage process requiring sensing environmental conditions and transducing signals to regulate expression of appropriate genes at balanced levels in
C. albicans
. Filamentous growth of
C. albicans
includes not only pseudohyphal, elongated yeast-like forms described for
Saccharomyces cerevisiae
, but true hyphae as well. Compared to most pathogenic fungi, the morphological response of
C. albicans
to environmental conditions is rapid. Germ tubes are produced within one hour of placing cells in appropriate conditions. The mechanisms employed by
C. albicans
to achieve this apparently advantageous spectrum of growth morphologies and optimized metabolic activities are poorly understood.
A feature of
C. albicans
growth that is correlated with pathogenicity in the oral cavity is the ability to transform from budding to filament-extending growth. Filamentous forms adhere more readily to buccal epithelial cells than budding yeasts, and histologically are a prominent feature of invasion of the mucosa. In mucosal disease, filamentous forms, particularly true hyphae, invade the keratinized layer of differentiated, stratified squamous epithelium. True hyphae are septate, cylindrical structures with parallel sides that are formed by extension of germ tubes that emerge from yeasts in appropriate environmental conditions.
The relative contribution of yeast and filamentous forms to the pathogenesis of candidiasis is an unresolved issue. However, mutants that do not produce hyphae in vitro have reduced virulence in animal models (Ghannoum et al., 63 Infect. Immun. 4528-30 (1995); Lo et al., 90 CELL 939-49 (1997); Sobel et al., 44 Infect. Immun. 576-80 (1984)). Expression of hypha-specific virulence factors such as the hyphal wall protein (HWP1) adhesin gene (Staab et al., 283 Science 1535-38 (1999); Staab et
Preston Gates Ellis & Rouvelas Meeds LLP
Shahnan-Shah Khatol S
Swartz Rodney P
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