title: Comparison of bactericidal and cytotoxic activities of trichogin analogs.
abstract: Peptaibiotics are a group of membrane active peptides of fungal origin. They typically contain α-aminoisobutyric acid (Aib; 1-letter code, U) and other non-coded residues (Toniolo and Brückner, 2009; Neumann et al., 2015; Benedett et al., 1982) [1], [2], [3] stabilizing their helical structure. Peptaibols are peptaibiotics carrying a 1, 2-aminoalcohol at the C-terminus. When a fatty acid chain (of 8-10 carbon atoms) is present at their N-terminus, they are called lipopeptaibols (Toniolo et al., 2001; Degenkolb et al., 2003) [4], [5]. We found (Tavano et al., 2015) [6] that the lipopeptaibol trichogin displays no antibacterial effects up to 64 µM, against both Gram(-) and Gram(+) bacteria, but kills tumor and healthy human cells via a mechanism requiring both the C-terminal primary alcohol group and the N-terminal n-octanoyl moiety, with EC50s around 4-5 µM. However, the substitution of single Gly residues with Lys strongly improves anti-Gram(+) activity (Tavano et al., 2015; De Zotti, Biondi, Park et al., 2012; De Zotti, Biondi, Peggion et al., 2012) [6], [7], [8]. To further characterize the activity of trichogin analogs as antibiotics and cytotoxic agents, we here manipulated the peptide helix amphipathicity by means of two different substitutions: (i) Aib to Leu (De Zotti et al., 2012) [7] or (ii) multiple Gly to Lys changes (Tavano et al., 2015; De Zotti, Biondi, Park et al., 2012; De Zotti, Biondi, Peggion, Formaggio et al., 2012; De Zotti, Biondi, Peggion, De Poli et al., 2012) [6], [7], [8], [9]. The antibacterial activity against four commensal or opportunistic bacterial species and the cytotoxicity against a panel of 9 healthy and tumor-derived eukaryotic cell types (including erythrocytes) are reported as MIC and EC50 (MTS - [3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)]-2H-tetrazolium- reduction and LDH - lactate dehydrogenase - release assay).
authors: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors: Regina
authors: R
authors: Tavano
authors: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors: Giulia
authors: G
authors: Malachin
authors: Institute of Biomolecular Chemistry, CNR, Padova Unit, Department of Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy.
authors: Marta
authors: M
authors: De Zotti
authors: Institute of Biomolecular Chemistry, CNR, Padova Unit, Department of Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy.
authors: Cristina
authors: C
authors: Peggion
authors: Institute of Biomolecular Chemistry, CNR, Padova Unit, Department of Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy.
authors: Barbara
authors: B
authors: Biondi
authors: Institute of Biomolecular Chemistry, CNR, Padova Unit, Department of Chemistry, University of Padova, Via Marzolo 1, 35131 Padova, Italy.
authors: Fernando
authors: F
authors: Formaggio
authors: Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors: Emanuele
authors: E
authors: Papini
keywords: Antibaterial activity; Cytotoxicity; Peptaibols; Trichogin