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

  1. 1.
    SYSNO ASEP0550090
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleSemi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity
    Author(s) Hájek, Jan (MBU-M) ORCID
    Bieringer, S. (DE)
    Voráčová, Kateřina (MBU-M)
    Macho, Markéta (MBU-M) ORCID
    Saurav, Kumar (MBU-M) ORCID
    Delawská, Kateřina (MBU-M) ORCID
    Divoká, Petra (MBU-M)
    Fišer, R. (CZ)
    Mikušová, G. (CZ)
    Cheel, José (MBU-M) RID, ORCID
    Fewer, D.P. (FI)
    Vu, Dai Long (MBU-M) ORCID
    Paichlová, Jindřiška (MBU-M)
    Riepl, H. (DE)
    Hrouzek, Pavel (MBU-M) ORCID
    Source TitleRSC Advances. - : Royal Society of Chemistry
    Roč. 11, č. 49 (2021), s. 30873-30886
    Number of pages14 s.
    Languageeng - English
    CountryGB - United Kingdom
    Keywordsalga anabaena-laxa ; membrane permeabilization ; laxaphycin-b ; peptides ; trichormamides ; inhibition ; iturins
    Subject RIVCE - Biochemistry
    OECD categoryBiochemistry and molecular biology
    R&D ProjectsLO1416 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
    EF18_070/0010493 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
    Method of publishingOpen access
    Institutional supportMBU-M - RVO:61388971
    UT WOS000716004200001
    EID SCOPUS85118936489
    DOI10.1039/d1ra04882a
    AnnotationMicrobial 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.
    WorkplaceInstitute of Microbiology
    ContactEliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231
    Year of Publishing2022
    Electronic addresshttps://pubs.rsc.org/en/content/articlelanding/2021/ra/d1ra04882a
Number of the records: 1  

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