Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity

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http://hdl.handle.net/10138/336658

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Hajek , J , Bieringer , S , Voracova , K , Macho , M , Saurav , K , Delawska , K , Divoka , P , Fiser , R , Mikusova , G , Cheel , J , Fewer , D P , Vu , D L , Paichlova , J , Riepl , H & Hrouzek , P 2021 , ' Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity ' , RSC Advances , vol. 11 , pp. 30873-30886 . https://doi.org/10.1039/d1ra04882a

Titel: Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity
Författare: Hajek, Jan; Bieringer, Sebastian; Voracova, Katerina; Macho, Marketa; Saurav, Kumar; Delawska, Katerina; Divoka, Petra; Fiser, Radovan; Mikusova, Gabriela; Cheel, Jose; Fewer, David P.; Vu, Dai Long; Paichlova, Jindriska; Riepl, Herbert; Hrouzek, Pavel
Upphovmannens organisation: Department of Microbiology
Department of Food and Nutrition
Helsinki Institute of Sustainability Science (HELSUS)
Microbial Natural Products
Datum: 2021-09-16
Språk: eng
Sidantal: 14
Tillhör serie: RSC Advances
ISSN: 2046-2069
DOI: https://doi.org/10.1039/d1ra04882a
Permanenta länken (URI): http://hdl.handle.net/10138/336658
Abstrakt: 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 mu M for MIN A and 3.2 mu M 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 mu M) and the plant pathogen Alternaria alternata (0.6 mu M), 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 mu M) and A. alternata (MIC = 0.1-0.5 mu M), but with partial retention of the cytotoxic effect (similar to 10-20 mu M). However, lipopeptides with esterified free hydroxyl groups possessed substantially higher antifungal potencies, especially against A. alternata (MIC = 0.2-0.6 mu M), and greatly reduced or abolished cytotoxic activity (>20 mu M). Our findings pave the way for a generation of semi-synthetic variants of lipopeptides with improved and selective antifungal activities.
Subject: ALGA ANABAENA-LAXA
MEMBRANE PERMEABILIZATION
LAXAPHYCIN-B
PEPTIDES
TRICHORMAMIDES
INHIBITION
ITURINS
1182 Biochemistry, cell and molecular biology
Referentgranskad: Ja
Licens: cc_by_nc
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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