Oral manifestations are widely regarded as important markers of the natural history and progression HIV infection and AIDS. Interestingly, already from the very early reports, one of the AIDS-defining opportunistic infections was oropharyngeal candidiasis (OPC) or thrush. Even in the post-HAART (Highly Active Antiretroviral Therapy) era, OPC still remains one of the most common AIDS defining illnesses and the most common opportunistic oral infection in HIV positive individuals. In HIV-infected patients, the opportunistc pathogenic fungus C. albicans is responsible for the majority of OPC episodes, as this otherwise normal commensal takes advantage of the underlying immunesuppression. Current antifungal therapy for the treatment of OPC has many shortcomings, due to the limited armamentarium of antifungal agents, the toxicity displayed by some of the current therapies and, principally, the emergence of resistance to most classes of antifungals. As conventional antifungal agents target processes that are essential for growth, they impose a high degree of selective pressure and the evolution of resistance is unavoidable. Indeed, resistance has been documented for all clinically used antifungal agents. Targeting pathogenetic mechanisms rather than essential processes represents a very attractive alternative for the development of new antibiotics. C. albicans virulence during oral infection is intimately linked to its ability to undergo morphogenetc conversion (filamentation) and to form biofilms. Thus, we surmise that filamentation and biofilm formation represent high value targets, yet clinically unexploited, for the development of novel anti-virulence approaches for the prevention and treatment of oral candidiasis. We have carried out high content screens and identified small molecule compounds that specifically inhibit C. albicans biofilm formation and filamentation. This application uses our leading compound identified during these screens - for which we have already confirmed lack of toxicity and potent in vivo activity - to fully validate inhibition of filamentation and biofilm formation as alternatie targets for the development of a novel anti-virulence approach against oral candidiasis, for which we will i) further characterize the in vitro activity of our lead anti-virulence compound, wih emphasis on minimizing the potential to induce resistance, ii) determine its in vivo activity in a mouse model of oral candidiasis, iii) determine the impact of treatment with our lead compound in the host immune responses during oral candidiasis, and iv) characterize its mechanism(- s) of action at the molecular level.

Public Health Relevance

This proposal constitutes a novel approach for the prevention and treatment of oropharyngeal candidiasis which remains the most common opportunistic oral infection in HIV/AIDS patients even in the post-HAART era. As opposed to conventional antifungals which target cell growth leading to resistance, we propose to specifically target virulence factors that are associated with infection. Results should ultimately lead to substantial decreases in morbidity, while simultaneously reducing healthcare costs.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DE023510-02
Application #
8629722
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78249
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