Restricted Research - Award List, Note/Discussion Page

Fiscal Year: 2014

2072  The University of Texas at San Antonio  (23632)

Principal Investigator: Lopez-Ribot, Jose

Total Amount of Contract, Award, or Gift (Annual before 2011): $ 367,500

Exceeds $250,000 (Is it flagged?): Yes

Start and End Dates: 4/1/13 <> 3/31/18

Restricted Research: YES

Academic Discipline: STCEID-PI-LOPEZ-RIBOT  

Department, Center, School, or Institute: South Texas Center for Emerging Infectious Diseases (STCEID)  

Title of Contract, Award, or Gift: Targeting Virulence Against Oral Candidiasis

Name of Granting or Contracting Agency/Entity: National Institutes of Health

Program Title: none
CFDA Linked: Oral Diseases and Disorders Research


Oral manifestations are considered 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), occurring in as many as 90% of patients with HIV/AIDS. Even after the introduction of highly active antiretroviral therapy (HAART), candidiasis has remained the most common opportunistic oral infection in HIV positive individuals, as OPC continues to represent a significant problem for patients in resource-limited settings and for those with poor immunologic response despite the initiation of HAART. Candida albicans, an otherwise normal commensal of human oral mucosal surfaces, remains the main causative agent of OPC in HIV-infected and AIDS patients. 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 all but inevitable. Indeed, resistance is 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 morphogenetic conversion within the body (filamentation) and its ability 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. This proposal is solidly anchored on work performed in our laboratory, spanning over the last three decades, on antifungal drug resistance, filamentation and biofilm formation, all of which are intimately linked to the pathogenesis of oral candidiasis. We performed the most comprehensive study to date on the epidemiology of molecular mechanisms of azole resistance and impact on oral yeast ecology in HIV-infected patients with OPC. Our C. albicans tet-NRG1 regulatable strain, in which morphological changes can be modulated both in vitro and in vivo, has provided the most compelling evidence to date linking filamentation and virulence. Our pioneer work on C. albicans biofims led to an increased appreciation of the role of these microbial communities in candidiasis, including high levels of resistance against clinically-used antifungals. Most recently, 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 systemic in vivo activity – to fully validate inhibition of filamentation and biofilm formation as alternative targets for the development of a novel anti-virulence approach against oral candidiasis. We propose the following specific aims: AIM 1. To further characterize the in vitro activity of our lead anti-virulence compound, with emphasis on minimizing the potential to induce resistance. AIM 2. To determine the efficacy and further characterize the in vivo activity of our lead anti-virulence compound against oral candidiasis. AIM 3. To determine the impact of treatment with our lead compound in the immunopathogenesis of oral candidiasis. AIM 4. To characterize the mechanism(-s) of action of the antivirulence compound at the molecular level.

Discussion: No discussion notes


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