Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity. Issue 49 (16th September 2021)

• Record Type: Journal Article
• Authors: Hájek, Jan; Bieringer, Sebastian; Voráčová, Kateřina; Macho, Markéta; Saurav, Kumar; Delawská, Kateřina; Divoká, Petra; Fišer, Radovan; Mikušová, Gabriela; Cheel, José; Fewer, David P.; Vu, Dai Long; Paichlová, Jindřiška; Riepl, Herbert; Hrouzek, Pavel
• Is Part Of: RSC advances. Volume 11:Issue 49(2021)
• Page Start: 30873
• Page End: 30886
• Publication Date: 2021-09-16
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1ra04882a
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : Both the substitution of free hydroxyl substituents and extending/branching of the fatty acid moiety improved the antifungal potency and limits the cytotoxicity of cyanobacterial cyclic lipopeptides puwainaphycin/minutissamides. Abstract : Microbial cyclic lipopeptides are an important class of antifungal compounds with applications in pharmacology and biotechnology. However, the cytotoxicity of many cyclic lipopeptides limits their potential as antifungal drugs. Here we present a structure–activity relationship study on the puwainaphycin/minutissamide (PUW/MIN) family of cyclic lipopeptides isolated from cyanobacteria. PUWs/MINs with variable fatty acid chain lengths differed in the dynamic of their cytotoxic effect despite their similar IC50 after 48 hours (2.8 μM for MIN A and 3.2 μM for PUW F). Furthermore, they exhibited different antifungal potency with the lowest MIC values obtained for MIN A and PUW F against the facultative human pathogen Aspergillus fumigatus (37 μM) and the plant pathogen Alternaria alternata (0.6 μM), respectively. We used a Grignard-reaction with alkylmagnesium halides to lengthen the lipopeptide FA moiety as well as the Steglich esterification on the free hydroxyl substituents to prepare semi-synthetic lipopeptide variants possessing multiple fatty acid tails. Cyclic lipopeptides with extended and branched FA tails showed improved strain-specific antifungal activity against A. fumigatus (MIC = 0.5–3.8 μM) and A. alternata (MIC = 0.1–0.5 μM), but with partial retention of the cytotoxic effect (∼10–20 μM). However, lipopeptides with esterified free hydroxyl groups possessed substantially higher antifungal potencies, especially against A. alternata (MIC = 0.2–0.6 μM), and greatly reduced or abolished cytotoxic activity (>20 μM). Our findings pave the way for a generation of semi-synthetic variants of lipopeptides with improved and selective antifungal activities.