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

0550090 - MBÚ 2022 RIV GB eng J - Článek v odborném periodiku
Hájek, Jan - Bieringer, S. - Voráčová, Kateřina - Macho, Markéta - Saurav, Kumar - Delawská, Kateřina - Divoká, Petra - Fišer, R. - Mikušová, G. - Cheel, José - Fewer, D.P. - Vu, Dai Long - Paichlová, Jindřiška - Riepl, H. - Hrouzek, Pavel
Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity.
RSC Advances. Roč. 11, č. 49 (2021), s. 30873-30886. E-ISSN 2046-2069
Grant CEP: GA MŠMT(CZ) LO1416; GA MŠMT(CZ) EF18_070/0010493
GRANT EU: European Commission(CZ) Interreg 41 Czech-Bavaria
Institucionální podpora: RVO:61388971
Klíčová slova: alga anabaena-laxa * membrane permeabilization * laxaphycin-b * peptides * trichormamides * inhibition * iturins
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.036, rok: 2021
Způsob publikování: Open access
https://pubs.rsc.org/en/content/articlelanding/2021/ra/d1ra04882a

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.
Trvalý link: http://hdl.handle.net/11104/0325943