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Anticandidal Activity of Lipopeptides Containing an LL-37-Derived Peptide Fragment KR12
Malgorzata Anna Paduszynska1, Damian Neubauer1, Wojciech Kamysz1
1Department of Inorganic Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland.
Abstract:
Candidiasis belongs to common fungal infections and is usually mild and self-limiting. However, in patients with immunodeficiencies, it can transform into invasive infections with high mortality. Long-term antifungal treatment can lead to the emergence of resistance. The problem is further complicated by the development of fungal biofilm resistant to conventional antimicrobials. Due to a limited choice of available antifungals, the development of novel active agents, such as antimicrobial peptides (AMPs), is highly desirable. Human cathelicidin LL-37 is an intensively studied AMP with a confirmed broad spectrum of antimicrobial activities. Due to the relatively high costs of production, the design of shorter analogs of LL-37 has been recommended. In this study, we synthesized a KR12 amide, KRIVQRIKDFLR-NH2, and its 24 derivatives obtained by substitution with fatty acids. The compounds were tested for their antifungal potential. They exhibited activity against the Candida albicans, C. glabrata, C. tropicalis and C. lipolytica. Five compounds: C10-KR12-NH2, C12-KR12-NH2, C14-KR12-NH2, 2-butyloctanoic acid-KR12-NH2, and 4-phenylbenzoic acid-KR12-NH2 were highly active against planktonic cells. C14-KR12-NH2 demonstrated also activity against C. albicans biofilm cultured on polystyrene for 24, 48 and 72 h. Lipidation has proven to be an effective strategy for improving microbiological activity of the KR12-NH2 peptide.
Insights
Novel antimicrobial peptides (AMPs) were developed to combat drug-resistant fungal infections like candidiasis. Researchers found that modifying the peptide LL-37 with fatty acids enhanced its antifungal activity against Candida species.
Area of Science:
- Microbiology
- Biochemistry
- Medicinal Chemistry
Background:
- Candidiasis is a common fungal infection that can become life-threatening in immunocompromised individuals.
- Emerging antifungal resistance and biofilm formation necessitate the development of new therapeutic agents.
- Antimicrobial peptides (AMPs), like human cathelicidin LL-37, show broad-spectrum activity but face production cost challenges.
Purpose of the Study:
- To synthesize and evaluate shorter analogs of LL-37, specifically a KR12 amide and its lipidation derivatives.
- To assess the antifungal activity of these novel compounds against various Candida species, including planktonic cells and biofilms.
- To determine the efficacy of lipidation as a strategy to enhance the antimicrobial properties of KR12-NH2.
Main Methods:
- Synthesis of a KR12 amide peptide (KRIVQRIKDFLR-NH2) and 24 derivatives substituted with fatty acids.
- Antifungal susceptibility testing against planktonic cultures of *Candida albicans*, *C. glabrata*, *C. tropicalis*, and *C. lipolytica*.
- Evaluation of the most potent compounds against *C. albicans* biofilm formation on polystyrene over 24, 48, and 72 hours.
Main Results:
- Five lipidation derivatives (C10-KR12-NH2, C12-KR12-NH2, C14-KR12-NH2, 2-butyloctanoic acid-KR12-NH2, and 4-phenylbenzoic acid-KR12-NH2) exhibited significant activity against planktonic Candida cells.
- C14-KR12-NH2 demonstrated potent antifungal activity against *C. albicans* biofilms formed over extended periods (24-72 hours).
- Lipidation significantly improved the microbiological activity of the parent KR12-NH2 peptide.
Conclusions:
- Fatty acid conjugation is an effective strategy to enhance the antifungal potency of KR12-NH2 peptide analogs.
- The developed lipidated peptides show promise as novel therapeutic agents against challenging Candida infections, including biofilms.
- Further research into these AMP derivatives could lead to new treatments for invasive fungal diseases.
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