Therapeutic agents that inhibit the tup1 pathway

Details Therapeutic agents that inhibit the tup1 pathway Therapeutic agents that inhibit the tup1 pathway

2002-09-10

2004-04-13

Ketter, James (Department: 1636)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S254220, C435S255400

Reexamination Certificate

active

06720151

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates generally to an approach for developing pharmaceuticals and treatment protocols that are effective against Candida-associated pathologies.
Fungal diseases have become a major medical problem and are growing in severity, given the rising incidence of immunosuppression associated with AIDS, diabetes, cancer therapies, and organ transplantation, among other conditions. Debilitated patients thus affected are especially susceptible to fungal pathogens, most of which are opportunists.
The yeast Candida can exist both as a non-virulent colonizer (commensal) and as a pathogen. Candidiasis is increasingly widespread, with hospitalized and immunocompromised patients at greatest risk, and has become the sixth most common form of pathogenic infection. Systemic Candida infections may be lethal, with a mortality rate of 50% in adults and up to 65% in infants. Reviewed in Pfaller (1996); see also Colombo et al. (1999). The risk of death from systemic infection most strongly correlates with the time between the first detected infection and the onset of anti-fungal treatment. Pacheco-Rios et al. (1997).
The pathogenic success of Candida depends in part upon phenotypic plasticity. The most prominent Candida pathogen,
C. albicans,
exhibits a bud-hypha phenotype transition that occurs en masse, in response to various stimuli, and provides
C. albicans
with the capacity to penetrate tissue and to disseminate. Odds (1997).
Candida albicans
also undergoes spontaneous, reversible, high frequency switching of phenotypes, which does not occur en masse.
More specifically,
C. albicans
may switch reversibly between a phenotype characterized by white colonies and a phenotype characterized by opaque colonies. Soll (1992). This white/opaque switching occurs at higher frequencies in isolates from deep versus superficial mycoses, Jones et al. (1994), at higher frequencies in infecting versus commensal isolates from the oral cavity, Hellstein et al. (1993), within sites of infection, Soll et al. (1987), (1988), and within sites of commensalism, Soll (1992). Switching also has been shown to regulate virulence in animal models. Kvaal et al. (1999).
High-frequency phenotypic switching in
C. albicans
involves the coordinated regulation of a battery of phase-specific genes. The gene products of several of these genes facilitate pathogenesis, Soll (1992) and Soll (1996). These products include secreted aspartyl proteinases, Hube et al. (1994), Morrow et al. (1992), (1993) and White et al. (1993), and drug resistance proteins, Balan et al. (1997).
Switching provides a mechanism for enhancing pathogenesis via generation of phenotypic plasticity. Thus, switching results in antigenic variability on the yeast cell surface. No single phenotypic trait has been found to be responsible for Candida pathogenesis, however. Moreover, uncertainty has surrounded the extent of overlap in respective regulatory circuitry for the switching event (white⇄opaque) and the dimorphism event (hypha⇄budding cell), as well as the significance of such overlap to Candida pathogenesis.
SUMMARY OF THE INVENTION
With the emergence of drug-resistant Candida strains and a growing population of immunocompromised individuals, there is an mounting need to find new treatments for candidiasis.
In light of this need and others, the present invention has provided, in one aspect, a method for screening a therapeutic agent, comprising subjecting a first Candida culture to the agent and then determining the impact thereof on expression of a gene in the TUP1 pathway, such as SAP3, OP4 and TUP1 itself, whereby decreased expression of the gene is predictive of efficacy for said agent against candidiasis. In a preferred embodiment, the aforementioned determination comprises gauging expression of the gene by reference to the level of Tup1 protein or TUP1 transcript in the first culture.


REFERENCES:
patent: 6433137 (2002-08-01), Johnson et al.
patent: 2002/0142468 (2002-10-01), Sundstrom
International Search Report for PCT/US02/25973 dated Feb. 20, 2003.
Balan, Inga et al., “TheCandida albicansCDR3 Gene Codes for an Opaque-Phase ABC Transporter,”Journal of Bacteriology, Dec. 1997, pp. 7210-7218, vol. 179, No. 23.
Bedell, Glenn et al., “Effects of Low Concentrations of Zinc on the Growth and Dimorphism of Candida albicans: Evidence for Zinc-Resistant and -Sensitive Pathways for Mycelium Formation,”Infection and Immunity, Oct. 1979, pp. 348-354, vol. 26, No. 1., United States.
Braun, B. et al., “TUP1, CPH1 and EFG1 Make Independent Contributions to Filamentation in Candida albicans,”The Genetics Society of America, May 2000, pp. 57-67, 155, United States.
Bruan, B. et al., “Identification and Characterization of TUP1-Regulated Genes in Candida albicans,”The Genetics Society of America, Sep. 2000, pp. 31-44, 156, United States.
Care, R.S. et al., “The MET3 promoter: a new tool for Candida albicans molecular genetics,”Molecular Microbiology, 1999, pp. 792-798, vol. 34(4), Blackwell Science Ltd.
Colombo, A. et al., “High Rate of non-albicans Candidemia in Brazilian Tertiary Care Hospitals,”Diagn Microbiol Infect Dis, 1999, pp. 281-286, vol. 34, Elsevier Science, Inc., United States.
Hellstein, J. et al., “Genetic Similarity and Phenotypic Diversity of Commensal and Pathogenic Strains of Candida albicans isolated from the Oral Cavity,”Journal of Clinical Microbiology, Dec. 1993, pp. 3190-3199, vol. 31, No. 12, American Society of Microbiology, United States.
Hube, B., et al., “Expression of seven members of the gene family encoding secretory aspartyl proteinases in Candida albicans,”Molecular Microbiology, 1994, pp. 87-99, vol. 14(1).
Jabet, C. et al., “Characterization of the N-terminal Domain of the Yeast Transcriptional Repressor Tup1,”The Journal of Biological Chemistry, Mar. 24, 2000, pp. 9011-9018, vol. 275, No. 12, American Society for Biochemistry and Molecular Biology., Inc., United States.
Kvaal, C. et al., “Misexpression fo the Opaque-Phase-Specific Gene PEP1 (SAP1) in the White Phase of Candida albicans Confers Increased Virulence in a Mouse Model of Cutaneous Infection,”Infection and Immunity, Dec. 1999, pp. 6652-6662, vol. 67, No. 12, American Society for Microbiology, United States.
Lipshutz, R. et al. “High density synthetic oligonucleotide arrays,”Nature Genetics Supplement, Jan. 1999, pp. 20-24, vol. 21, Nature America Inc., United States.
Morrow, B. et al., “Transcription of the Gene for a Pepsinogen, PEP1, is Regulated by White-Opaque Switching in Candida albicans,”Molecular and Cellular Biology, Jul. 1992, pp. 2997-3005, vol. 12, No. 7.
Morrow, B., et al. “Coordinate Regulation of Two Opaque-Phase-Specific Genes during White-Opaque Switching in Candida albicans,”Infection and Immunity, May 1993, pp. 1823-1828, vol. 61, No. 5, American Society for Microbiology, United States.
Odds, F.C., “Switch of Phenotype as an escape mechanism of the Intruder,”Mycoses, 1997, pp. 9-12, vol. 40, Supplement 2, United States.
Pacheco-Rios, A. et al., “Mortality Associated with Systematic Candidlasis in Children,”Archives of Medical Research, 1997, pp. 229-232, vol. 28, No. 2, Instituto Mexicano de Seguro Social, Mexico.
Pfaller, M., “Nosocomial Candidiasis: Emerging Species, Reservoirs, and Modes of Transmission,”Clinical Infectious Diseases, May 1996, pp. 589-594, vol. 22, Supplement 2, University of Chicago Press, United States.
Soll, D. et al., “High-Frequency Switching in Candida Strains Isolated from Vaginitis Patients,”Journal of Clinical Microbiology, Sep. 1987, pp. 1611-1622, vol. 25, No. 9, American Society for Microbiology, United States.
Soll, D. et al., “Multiple Candida Strains in the Course of a Single Systemic Infection,”Journal of Clinical Microbiology, Aug. 1988, pp. 1448-1459, vol. 26, No. 8, American Society for Microbiology, United States.
Soll, D., “High-Frequency Switching in Candida albicans,”Clinical Microbiology Reviews, Apr. 1992, pp. 183-203, vol. 5, No. 2., American Society for Microbiology, United States.
Soll , D., “The Emerging Molecular Biology of Switching

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