Aspergillus fumigatus acetyl coenzyme-A carboxylase genes...

Details Aspergillus fumigatus acetyl coenzyme-A carboxylase genes... Aspergillus fumigatus acetyl coenzyme-A carboxylase genes...

1999-12-30

2003-02-04

Guzo, David (Department: 1636)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Recombinant dna technique included in method of making a...

C435S320100, C435S471000, C435S325000, C435S252300, C435S254300, C536S023100

Reexamination Certificate

active

06514726

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to acetyl coenzyme A carboxylase genes of the fungus
Aspergillus fumigatus
and their use in identifying antifungal agents.
BACKGROUND OF THE INVENTION
The enzyme acetyl coenzyme A carboxylase (ACCase) is responsible for synthesizing malonyl CoA from acetyl CoA. ACCase is essential for synthesis of fatty acids.
By way of background, the Fungi Kingdom consists of two divisions, the Eumycota and Myxomycota or the true fungi and slime molds, respectively. The true fungi are those species that are hyphal or are clearly related to species that are hyphal, possess cell walls throughout most or all of their life cycle, and are exclusively absorptive in their function. The slime molds are organisms that do not form hyphae, lack cell walls during the phase in which they obtain nutrients and grow and are capable of ingesting nutrients in particulate form by phagocytosis.
The two most important classes of true fungi in which most species produce motile cells, known as zoospores, are the Oomycetes, and the Chytridiomycetes. The fungi that lack zoospores are classified according to the sexual phase of the fungal life cycle. The sexual process leads to the production of characteristic spores in the different groups. The fungi that form zygospores are classified as Zygomycetes, those that form ascospores are classified as Ascomycetes, and those forming basidiospores are classified as Basidiomycetes. There are also many species, recognizable as higher fungi through the presence of cell walls in their hyphae, that produce asexual spores but lack a sexual phase. These are known as Deuteromycetes, and details of their asexual sporulation are used to classify them. A representative member of the Deuteromycetes includes
Candida albicans.
These species are extensively reviewed in “The Fungi” (Ed M J Carlile and S C Watkinson 1994 Acad Press Ltd) and “The Growing Fungus” (Ed. N A R Gow and G M Gadd, 1995, Chapman and Hall).
Yeast are fungi that are normally unicellular and reproduce by budding although some will, under appropriate conditions, produce hyphae, just as some normally hyphal fungi may produce a yeast phase. The best known of all yeasts is
Saccharomyces cerevisiae,
which is a member of the Ascomycetes species. It is commonly regarded as a diploid yeast since mating usually soon follows ascospore germination. However, single cells can be used to establish permanently haploid cultures.
Fungal and other mycotic pathogens are responsible for a variety of diseases in humans, animals and plants. Fungal infection is also a significant problem in veterinary medicine. Some of the fungi that infect animals can be transmitted from animals to humans. Fungal infections or infestations are also a very serious problem in agriculture with fungicides being employed to protect vegetable and fruit and cereal crops. Fungal attack of wood products is also of major economic importance. Additional products that are susceptible to fungal infestation include textiles, plastics, paper and paint. Some of these fungal targets are extensively reviewed in WO 95/11969.
Statistics show that the incidence of fungal infections has doubled from the 1980's to the 1990's, and infections of the blood stream have increased fivefold with an observed mortality of 50% (Tally et al., 1997, Int. Conference Biotechnol Microb. Prods: Novel Pharmacol. Agrobiol. Activities, Williamsburg, Va. Abstr S5 p19). These include those fungal infections, such as candidiasis, to which all individuals are susceptible, but also infections such as cryptococcosis and aspergillosis, which occur particularly in patients of compromised immune status.
By way of example, the yeast
Candida albicans
(
C. albicans
) has been shown to be one of the most pervasive fungal pathogens in humans. It has the capacity to opportunistically infect a diverse spectrum of compromised hosts, and to invade many diverse tissues in the human body. It can in many instances evade antibiotic treatment and the immune system. Although
Candida albicans
is a member of the normal flora of the mucous membranes in the respiratory, gastrointestinal, and female genital tracts, in such locations, it may gain dominance and be associated with pathologic conditions. Sometimes it produces progressive systematic disease in debilitated or immunosuppressed patients, particularly if cell-mediated immunity is impaired. Sepsis may occur in patients with compromised cellular immunity, e.g., those undergoing cancer chemotherapy or those with lymphoma, AIDS, or other conditions. Candida may produce bloodstream invasion, thrombophlebitis, endocarditis, or infection of the eyes and virtually any organ or tissue when introduced intravenously, e.g., via tubing, needles, narcotics abuse etc.
Candida albicans
has been shown to be diploid with balanced lethals, and therefore probably does not go through a sexual phase or meiotic cycle. This yeast appears to be able to spontaneously and reversibly switch at high frequency between at least seven general phenotypes. Switching has been shown to occur not only in standard laboratory strains, but also in strains isolated from the mouths of healthy individuals.
Nystatin, ketoconazole, and amphotericin B are drugs that have been used to treat oral and systemic Candida infections. However, orally administered nyastin 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, ranging from nausea and vomiting to kidney damage and toxicities occur even at therapeutic concentrations. While ketoconazole and other azole antifungals exhibit significantly lower toxicity, their mechanism of action, through 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. These adverse effects mean that their use is generally limited to the treatment of topical or superficial infections. In addition, resistance to these compounds is emerging and may pose a serious problem in the future. The more recently developed triazole drugs, such as fluconazole, are believed by some to have fewer side effects but are not completely effective against all pathogens.
Invasive aspergillosis, caused by
Aspergillus fumigatus
(
A. fumigatus
) has also become an increasingly opportunistic infection. There has been a 14-fold increase in its incidence during the past 12 years as detected by autopsy, and only two drugs are available that are effective in its treatment, neither of which is completely satisfactory. Amphotericin B needs to be given intravenously and has a number of toxic side effects. Itraconazole, which can be given orally is often prescribed imprudently, encouraging the emergence of resistant fungal strains (Dunn-Coleman and Prade, Nature Biotechnology, 1998, 16: 5). Resistance is also developing to synthetic azoles (such as fluconazole and flucytosine), and the natural polyenes (such as amphotericin B) are limited in use by their toxicity.
Fungicide resistance generally develops when a fungal cell or fungal population that originally was sensitive to a fungicide becomes less sensitive by heritable changes after a period of exposure to the fungicide.
In certain applications, such as agriculture, it is possible to combat resistance through alteration of fungicides or the use of fungicide mixtures. To prevent or delay the build up of a resistant pathogen population, different agents that are effective against a particular disease must be available. One way of increasing the number of available agents is to search for new site-specific inhibitors.
Consequently, antifungal drug discovery efforts have been directed at components of the fungal cel

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