1272 - Efficacy of a Non-Peptide, Small Molecule Mimic of Host Defense Proteins in Mouse Models of Disseminated Candidiasis and Aspergillosis.

The ePoster content is available to users who are logged in.<br><br>Please log in and then come back here to use this button.

Presenting Author(s)

RS

Richard W. Scott

Vice President, Research
Fox Chase Chemical Diversity Center, Inc.
Doylestown, Pennsylvania
Disclosure: Fox Chase Chemical Diversity Center (Employee)

Co-Author(s)

SB

Simon DP Baugh

Dr
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: Fox Chase Chemical Diversity Center (Employee)
KF

Katie B. Freeman

Director
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
DW

Damian G Weaver

Senior Associate Scientist
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
AC

Anna L Chaly

Senior Research Associate
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
DW

David B Whitman

Research Investigator
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
ST

Sandeep Thanna

Research Investigator
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
GD

Gill Diamond

Professor
University of Louisville School of Dentistry
Louisville, Kentucky
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
PN

Phung Nguyen

Research Investigator
University of North Texas Health Science Center
Fort Worth, Texas
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
AD

Ashley Deviney

Research Investigator
University of north Texas Health Science Center
Fort Worth, Texas
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
WW

William J Weiss

Director
University of North Texas Health Science Center
Fort Worth, Texas
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
MP

Mark E Pulse

Associate Director
University of North Texas Health Science Center
Fort Worth, Texas
Disclosure: Fox Chase Chemical Diversity Center (Independent Contractor)
AR

Allen B Reitz

CEO
Fox Chase Chemical Diversity Center
Doylestown, Pennsylvania
Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Background: We are developing a series of small nonpeptide mimics of host defense proteins (smHDPs) for antifungal applications. MICs < 0.1 µg/ ml have been demonstrated against multiple yeast and mold species. Their potential therapeutic utility has been evaluated in animal models of disseminated fungal infections.

Methods: Susceptibility testing against clinical isolates of Candida albicans (CA) and Aspergillus fumigatus (AF) was done according to CLSI guidelines. Cytotoxicity (CC₅₀) in mouse 3T3 and human HepG2 cells was determined in an MTS assay (Promega Cell Titer 96). For candidiasis, neutropenic CD-1 mice were infected IV with 3.5 x 10⁴ CFU CA and test agents were administered subcutaneously (SC) once (QD) or twice (BID) daily beginning 2 hrs post-infection (PI). The positive control was fluconazole (20 mg/kg PO QD). Kidney burdens were measured at 24 hrs PI (n = 5/grp) and survival was measured at 2 weeks after 5 days of treatment (n = 8/grp). For aspergillosis, neutropenic CD-1 mice were infected IV with 4.5 log10 spores AF and test agents were administered SC BID for 5 days beginning 24 hrs PI. The positive control was posaconazole (20 mg/kg PO QD). Liver and kidney fungal burdens were measured 24 hrs after the last dose (n = 10/grp).

Results: The lead smHDP, FC-5096, has MICs of 0.08 and 0.024 ug/ml, respectively, against the CA and AF clinical isolate strains used in the mouse efficacy studies. Selectivity for antifungal vs. mammalian cell cytotoxicity (MIC/CC₅₀) was >1,000 fold. In the disseminated candidiasis model, FC-5096 significantly reduced fungal kidney burdens relative to untreated mice to levels found at treatment onset (P < 0.0001). Full survival over 2 weeks was observed after 5 days of BID treatment with FC-5096. All untreated mice succumbed between days 3 – 6 PI. Efficacy was comparable to fluconazole. In the disseminated aspergillosis model, FC-5096 produced up to 2.5 log10 reductions in fungal liver burdens and efficacy was significantly better than posaconazole (P = 0.0251). In kidney, both FC-5096 and posaconazole caused > 1.6 log10 reductions in fungal burdens that exceeded the limit of detection.

Conclusion: The high antifungal potency, low cytotoxicity and robust in vivo efficacy support further study of FC-5096 for clinical development.