In vivo imaging of the activity of host defense peptide mimetics in a mouse model of invasive candidiasis

Gill Diamond,Rezwana Parveen,Lisa Ryan,Katie Freeman,Amy Hise,Richard Scott

doi:10.3390/ecmc-4-05628

Abstract

Systemic fungal infections are increasingly common, especially in immune compromised patients. Even with newly developed drugs, there remain issues of limited spectrum, side effects, and the development of resistance. Host defense peptides (HDPs) have been examined recently for their utility as therapeutic antifungals, especially due to the low levels of resistance that develop. Unfortunately, the peptides exhibit poor pharmacologic properties in vivo. We have demonstrated the potent activity of nonpeptidic compounds that mimic HDPs in both structure and function against clinical strains of Candida albicans associated with oral and invasive candidiasis in mouse models. However, to test numerous compounds in vivo requires large numbers of mice, with multiple time points, and requires immunosuppression of the mice using cyclophosphamide, which can influence pharmacological parameters. We have identified a strain of mouse that develops invasive candidiasis without the need for immunosuppressive drugs. When we infect these mice with a strain of C. albicans that constitutively expresses Red Fluorescent Protein, we can quantify the infection in real time by in vivo imaging. We can further observe the reduction in fluorescence in infected mice after treatment with an HDP mimetic. Together our results demonstrate a novel in vivo method for screening new antifungal drugs.

Highlights

Antimicrobial peptides Short, generally cationic, broad-spectrum antimicrobial proteins Found at mucosal surfaces– Skin secretions in fish and amphibians – Oral cavity, trachea, small intestine, female reproductive tract in mammals Found in myeloid cells– Neutrophils, alveolar macrophages Types of AMPs Linear– Amphipathic a-helical Cysteine-rich – b-sheet
We have demonstrated the potent activity of nonpeptidic compounds that mimic Host defense peptides (HDPs) in both structure and function against clinical strains of Candida albicans associated with oral and invasive candidiasis in mouse models
When we infect these mice with a strain of C. albicans that constitutively expresses Red Fluorescent Protein, we can quantify the infection in real time by in vivo imaging

Summary

Introduction

We have demonstrated the potent activity of nonpeptidic compounds that mimic HDPs in both structure and function against clinical strains of Candida albicans associated with oral and invasive candidiasis in mouse models. We have identified a strain of mouse that develops invasive candidiasis without the need for immunosuppressive drugs. When we infect these mice with a strain of C. albicans that constitutively expresses Red Fluorescent Protein, we can quantify the infection in real time by in vivo imaging. We can further observe the reduction in fluorescence in infected mice after treatment with an HDP mimetic.

Results

Conclusion