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

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dc.contributor.author Hajek, Jan
dc.contributor.author Bieringer, Sebastian
dc.contributor.author Voracova, Katerina
dc.contributor.author Macho, Marketa
dc.contributor.author Saurav, Kumar
dc.contributor.author Delawska, Katerina
dc.contributor.author Divoka, Petra
dc.contributor.author Fiser, Radovan
dc.contributor.author Mikusova, Gabriela
dc.contributor.author Cheel, Jose
dc.contributor.author Fewer, David P.
dc.contributor.author Vu, Dai Long
dc.contributor.author Paichlova, Jindriska
dc.contributor.author Riepl, Herbert
dc.contributor.author Hrouzek, Pavel
dc.date.accessioned 2021-11-24T07:40:01Z
dc.date.available 2021-11-24T07:40:01Z
dc.date.issued 2021-09-16
dc.identifier.citation 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
dc.identifier.other PURE: 170419870
dc.identifier.other PURE UUID: 1e763be4-27e2-476c-9d99-fd3ceb639e84
dc.identifier.other WOS: 000716004200001
dc.identifier.other ORCID: /0000-0003-3978-4845/work/103723815
dc.identifier.uri http://hdl.handle.net/10138/336658
dc.description.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 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. en
dc.format.extent 14
dc.language.iso eng
dc.relation.ispartof RSC Advances
dc.rights cc_by_nc
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject ALGA ANABAENA-LAXA
dc.subject MEMBRANE PERMEABILIZATION
dc.subject LAXAPHYCIN-B
dc.subject PEPTIDES
dc.subject TRICHORMAMIDES
dc.subject INHIBITION
dc.subject ITURINS
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity en
dc.type Article
dc.contributor.organization Department of Microbiology
dc.contributor.organization Department of Food and Nutrition
dc.contributor.organization Helsinki Institute of Sustainability Science (HELSUS)
dc.contributor.organization Microbial Natural Products
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1039/d1ra04882a
dc.relation.issn 2046-2069
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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