Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-02-12
2004-06-08
Marschel, Ardin H. (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S006120, C536S024300, C536S024310, C536S024320, C536S024330
Reexamination Certificate
active
06747137
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to isolated nucleic acids and polypeptides derived from
Candida albicans
that are useful as molecular targets for diagnostics, prophylaxis and treatment of pathological conditions, as well as materials and methods for the diagnosis, prevention, and amelioration of pathological conditions resulting from fungal infection.
BRIEF DESCRIPTION OF THE SEQUENCE LISTING
Incorporated herein by reference in its entirety is a Sequence Listing comprising SEQ ID No. 1 to SEQ ID NO:28208. The Sequence Listing is contained on a CD-ROM, three copies of which are filed, the Sequence Listing being in a computer-readable ASCII file named “cand09.2001.txt”, created on Sep. 14, 2001 and of 38,660 bytes in size, in IBM-PC Windows®NT v4.0 format.
BACKGROUND OF THE INVENTION
Candida albicans
is a dimorphic fungus which has both a yeast-like growth habit and a filamentous form consisting of both hyphae and pseudohypae. The fungus is a member of the normal surface flora of most individuals. Although no sexual state has been described for
C. albicans
, the genome is diploid in most strains (Whelan, W L et al. (1980)
Mol. Gen. Genet.
180: 107-113; Whelan, W L and Magee, P T (1981)
J. Bacteriol.
145: 896-903; Poulter, R. (1982)
J. Bacteriol.
152: 969-975) and rearranges relatively frequently (Rustchenko-Bulgac E P, et al (1990)
J Bacteriol.
172: 1276-1283; Barton, R C and Scherer, S (1994)
J. Bacteriol .
176: 756-763). In addition, one non-universal decoding is known in which a leucine codon (CUG) is translated as a serine (Leuker et al. (1994),
Mol. Gen. Genet.
245: 212-217; Santos et al., (1993)
EMBO Journal
12:607-616). This creates difficulties in the application of the powerful genetic and molecular methods used in Saccharomyces and Schizosaccharomyces.
C. albicans
exists as part of the normal microbial flora in humans, but can produce opportunistic infections ranging from topical infections such as oral thrush to life-threatening disseminated mycoses (Ampel, N M (1996)
Emerg. Infect. Dis.
2: 109-116). Candida is a major cause of nosocomial infections and was found to account for more than 75% of all fungal nosocomial infections reported by NNIS (National Nosocomial Infections Surveillance) hospitals from 1980-1990 in which fungi alone accounted for 7.9% of all nosocomial infections (Beck-Sagu, C M and Jarvis, W R (1993)
J. Infect. Dis.
167: 1247-1251). Although the source of Candida in infections is frequently traced to endogenous sources on the patient, it has also been traced to exogenous sources in the hospital environment including contaminated solutions and equipment (Shetertz, R J et al. (1992)
J. Pediatr.
120: 455-461; Weems, J J et al. (1987)
J. Clin. Microbiol.
1925: 1029-1032), and health care workers (Hunter, P R et al (1990)
J. Med Vet Mycol.
28: 317-325; Burnie, J P (1986)
J. Hosp. Infect.
8: 1-4; Doebbeling, B N et al. (1991)
J. Clin. Microbiol.
29: 1268-1270). Numerous investigations into the molecular basis of pathogenicity have been made implicating the hyphal form (Lo, H J et al. (1997)
Cell
90:939-949), surface molecules including adhesins (Fukazawa Y and Kagaya K (1997)
J Med Vet Mycol
35:87-99), and ATP-binding cassette-containing multi-drug resistance proteins (Prasad, R et al.(1995)
Curr. Genet.
27: 320-329).
The antimicrobials currently in use against Candida are generally of three types: azoles, such as iluconazole, itraconazole, and clotrimazole; polyenes, such as amphotericin B and nystatin; and 5-fluorocytosine. However, invasive infections are treated primarily with fluconazole, amphotericin B, and 5-fluorocytosine, although the latter two compounds have significant toxic side effects. The development of resistance to iluconazole by
C. albicans
has been noted by a number of researchers (Redding, S (1994)
Clin. Infect. Dis.
18: 339-346; Sargeorzan, J A (1994)
Am. J. Med.
97: 339-346; Revankar, S G et al. (1996)
J. Infect. Dis.
174: 821-827; Marr, K A et al. (1997)
Clin. Infect. Dis
25: 908-910). Relatively short treatments seem to result in few if any resistant isolates, but extended treatments including prophylactic treatments such as are required among immunocompromised and AIDS patients, result in the appearance of fluconazole-resistant strains (Johnson, E M (1995)
J. Antimicrob. Chemother.
35: 103-114). Development of fluconazole-resistance has been observed to be associated with the development of amphotericin-resistance (Vazquez, J A (1996)
Antimicrob. Agents Chemother.
40: 2511-2516; Nolte, F S et al. (1997)
Antimicrob. Agents Chemother.
41: 196-199; White, T C (1997)
ASM News
63: 427-433) consistent with the action of both drugs on ergosterol in the membrane.
The difficulty in diagnosing
C. albicans
infections, the limited spectrum of current therapeutic drugs and the development of drug resistant strains of
C. albicans
provide the rationale for the identification of targets for more rapid and effective methods of identification, prevention, and treatment of candidiasis. The elucidation of the genome of
C. albicans
would enhance the understanding of how
C. albicans
, as well as other fungi, causes invasive disease and how best to combat fungal infection.
SUMMARY OF THE INVENTION
The present invention fulfills the need for diagnostic tools and therapeutics by providing fungal-specific compositions and methods for detecting, treating, and preventing fungal infection, in particular
C. albicans
infection. They also have use as biocontrol agents for plants.
The present invention encompasses isolated nucleic acids and polypeptides derived from
C. albicans
that are useful as reagents for diagnosis of fungal disease, components of effective antifungal vaccines, and/or as targets for antifungal drugs including anti-
C. albicans
drugs. They can also be used to detect the presence of
C. albicans
and other Candida species in a sample; and in screening compounds for the ability to interfere with the
C. albicans
life cycle or to inhibit
C. albicans
infection.
More specifically, this invention features compositions of nucleic acids corresponding to entire coding sequences of
C. albicans
proteins, including surface or secreted proteins or parts thereof, nucleic acids capable of binding mRNA from
C. albicans
proteins to block protein translation, and methods for producing
C. albicans
proteins or parts thereof using peptide synthesis and recombinant DNA techniques. This invention also features antibodies and nucleic acids useful as probes to detect
C. albicans
infection. In addition, vaccine compositions and methods for the protection or treatment of infection by
C. albicans
are within the scope of this invention.
The nucleotide sequences provided in SEQ ID NO: 1-SEQ ID NO: 14103, a fragment thereof, or a nucleotide sequence at least about 99.5% identical to a sequence contained within SEQ ID NO: 1-SEQ ID NO: 14103 may be “provided” in a variety of medias to facilitate use thereof. As used herein, “provided” refers to a manufacture, other than an isolated nucleic acid molecule, which contains a nucleotide sequence of the present invention, i.e., the nucleotide sequence provided in SEQ ID NO: 1-SEQ ID NO: 14103, a fragment thereof, or a nucleotide sequence at least about 99.5% identical to a sequence contained within SEQ ID NO: 1-SEQ ID NO: 14103. Uses for and methods for providing nucleotide sequences in a variety of media is well known in the art (see e.g., EPO Publication No. EP 0 756 006).
In one application of this embodiment, a nucleotide sequence of the present invention can be recorded on computer readable media. As used herein, “computer readable media” refers to any media which can be read and accessed directly by a computer. Such media include, but are not limited to: magnetic storage media, such as floppy discs, hard disc storage media, and magnetic tape; optical storage media such as CD-ROM; electrical storage media such as RAM and ROM; and hybrids of these categories such as magnetic/optical storage media. A person skilled in the art can readi
Bush David
Weinstock Keith G.
Genome Therapeutics Corporation
Genome Therapeutics Corporation
Marschel Ardin H.
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