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Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity
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SYSNO ASEP 0550090 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Semi-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) ORCIDSource Title RSC Advances. - : Royal Society of Chemistry
Roč. 11, č. 49 (2021), s. 30873-30886Number of pages 14 s. Language eng - English Country GB - United Kingdom Keywords alga anabaena-laxa ; membrane permeabilization ; laxaphycin-b ; peptides ; trichormamides ; inhibition ; iturins Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects LO1416 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_070/0010493 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000716004200001 EID SCOPUS 85118936489 DOI 10.1039/d1ra04882a Annotation 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2022 Electronic address https://pubs.rsc.org/en/content/articlelanding/2021/ra/d1ra04882a
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