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.
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.
|Vila, Taissa; Lopez-Ribot, Jose L (2016) Screening the ""Pathogen Box"" for the Identification of Candida albicans Biofilm Inhibitors. Antimicrob Agents Chemother :|
|Vila, Taissa; Romo, Jesus A; Pierce, Christopher G et al. (2016) Targeting Candida albicans filamentation for antifungal drug development. Virulence :1-9|
|Uppuluri, Priya; Lopez-Ribot, Jose L (2016) Go Forth and Colonize: Dispersal from Clinically Important Microbial Biofilms. PLoS Pathog 12:e1005397|
|Montelongo-Jauregui, Daniel; Srinivasan, Anand; Ramasubramanian, Anand K et al. (2016) An In Vitro Model for Oral Mixed Biofilms of Candida albicans and Streptococcus gordonii in Synthetic Saliva. Front Microbiol 7:686|
|Pierce, Christopher G; Chaturvedi, Ashok K; Lazzell, Anna L et al. (2015) A Novel Small Molecule Inhibitor of Candida albicans Biofilm Formation, Filamentation and Virulence with Low Potential for the Development of Resistance. NPJ Biofilms Microbiomes 1:|
|Vila, Taissa Vieira Machado; Chaturvedi, Ashok K; Rozental, Sonia et al. (2015) In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis. Antimicrob Agents Chemother 59:7611-20|
|Pierce, Christopher G; Srinivasan, Anand; Ramasubramanian, Anand K et al. (2015) From Biology to Drug Development: New Approaches to Combat the Threat of Fungal Biofilms. Microbiol Spectr 3:|
|Lara, Humberto H; Romero-Urbina, Dulce G; Pierce, Christopher et al. (2015) Effect of silver nanoparticles on Candida albicans biofilms: an ultrastructural study. J Nanobiotechnology 13:91|
|Srinivasan, Anand; Lopez-Ribot, Jose L; Ramasubramanian, Anand K (2015) Microscale microbial culture. Future Microbiol 10:143-6|
|Lopez-Ribot, Jose L (2014) Large-scale biochemical profiling of the Candida albicans biofilm matrix: new compositional, structural, and functional insights. MBio 5:e01781-14|
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