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Updated: Jun 29, 2025
RNA Interference in Ticks
Published on: January 20, 2011
Tryptophan End-Tagging Confers Antifungal Activity on a Tick-Derived Peptide by Triggering Reactive Oxygen Species
Court K Chiramba1, Dalton S Möller1, Christian D Lorenz2
1Department of Biochemistry, Genetics and Microbiology, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0002, South Africa.
Abstract:
WHO has identified several Candida species including Candida albicans as critical priority fungal pathogens due to greater infection prevalence and formation of recalcitrant biofilms. Novel antifungal agents are urgently needed, and antimicrobial peptides (AMPs) are being considered as potential alternatives, but inactivity in physiological salt environments, serum, and plasma often limits further therapeutic development. Tryptophan end-tagging is a strategy to overcome these limitations and is thought to selectively enhance membrane permeabilization in both fungal and bacterial plasma membranes. Here, we show that C-terminal tryptophan end-tagging of the tick-derived peptide Os-C transforms an inactive peptide into Os-C(W5), an antifungal peptide capable of preventing the formation of C. albicans biofilms. Mechanistic insight is provided by circular dichroism spectroscopy and molecular dynamics simulations, which demonstrate that tryptophan end-tagging alters the secondary structure of Os-C, while the latter reveals that end-tagging reduces interactions with, and insertion into, a model C. albicans membrane but promotes peptide aggregation on its surface. Interestingly, this leads to the induction of reactive oxygen species production rather than membrane permeabilization, and consequently, oxidative stress leads to cell wall damage. Os-C(W5) does not induce the hemolysis of human erythrocytes. Reduced cell adhesion and viability contribute to decreased biofilm extracellular matrix formation which, although reduced, is retained in the serum-containing medium. In this study, tryptophan end-tagging was identified as a promising strategy for enhancing the antifungal activity, including the biofilm inhibitory activity of Os-C against C. albicans in physiological salt environments.
Insights
Tryptophan end-tagging transformed an inactive peptide into a potent antifungal agent, Os-C(W5), effectively inhibiting Candida albicans biofilms. This novel strategy enhances peptide activity in physiological conditions without causing red blood cell damage.
Area of Science:
- Biochemistry
- Microbiology
- Drug Discovery
Background:
- Candida albicans is a priority fungal pathogen known for forming difficult-to-treat biofilms.
- Existing antifungal peptides often show limited efficacy in physiological environments like serum.
- Novel strategies are needed to develop effective antifungal agents against resistant fungal infections.
Purpose of the Study:
- To investigate the efficacy of tryptophan end-tagging as a strategy to enhance the antifungal activity of the Os-C peptide.
- To evaluate the potential of the modified peptide, Os-C(W5), in preventing Candida albicans biofilm formation.
- To elucidate the mechanism of action of Os-C(W5) against Candida albicans.
Main Methods:
- C-terminal tryptophan end-tagging of the Os-C peptide.
- Antifungal activity assays against Candida albicans biofilms.
- Circular dichroism spectroscopy and molecular dynamics simulations to study peptide structure and membrane interactions.
- Assessment of hemolytic activity against human erythrocytes.
- Analysis of reactive oxygen species production and cell wall damage.
Main Results:
- Tryptophan end-tagging converted the inactive Os-C peptide into an active antifungal agent, Os-C(W5).
- Os-C(W5) effectively inhibited Candida albicans biofilm formation and reduced cell adhesion and viability.
- The modified peptide induced reactive oxygen species production and cell wall damage, rather than direct membrane permeabilization.
- Os-C(W5) demonstrated no hemolytic activity against human erythrocytes.
- The peptide maintained efficacy in serum-containing medium.
Conclusions:
- Tryptophan end-tagging is a promising strategy to enhance the antifungal and anti-biofilm activity of peptides like Os-C.
- Os-C(W5) represents a potential therapeutic candidate for combating Candida albicans infections, particularly biofilms.
- The mechanism involves oxidative stress induction and cell wall damage, offering a novel approach to antifungal therapy.
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