Pentadecaibins I–V: 15-Residue Peptaibols Produced by a Marine-Derived Trichoderma sp. of the Harzianum Clade

Abstract

In the course of investigations on peptaibol chemodiversity from marine-derived Trichoderma spp., five new 15-residue peptaibols named pentadecaibins I–V (1–5) were isolated from the solid culture of the strain Trichoderma sp. MMS1255 belonging to the T. harzianum species complex. Phylogenetic analyses allowed precise positioning of the strain close to T. lentiforme lineage inside the Harzianum clade. Peptaibol sequences were elucidated on the basis of their MS/MS fragmentation and extensive 2D NMR experiments. Amino acid configurations were determined by Marfey’s analyses. The pentadecaibins are based on the sequences Ac-Aib1-Gly2-Ala3-Leu4-Aib/Iva5-Gln6-Aib/Iva7-Val/Leu8-Aib9-Ala10-Aib11-Aib12-Aib13-Gln14-Pheol15. Characteristic of the pentadecaibin sequences is the lack of the Aib-Pro motif commonly present in peptaibols produced by Trichoderma spp. Genome sequencing of Trichoderma sp. MMS1255 allowed the detection of a 15-module NRPS-encoding gene closely associated with pentadecaibin biosynthesis. Pentadecaibins were assessed for their potential antiproliferative and antimicrobial activities.

Acremopeptaibols A–F, 16-Residue Peptaibols from the Sponge-Derived Acremonium sp. IMB18-086 Cultivated with Heat-Killed Pseudomonas aeruginosa

“…The apt cluster encoded four genes (Table S5), including the 58 kbp hybrid PKS-NRPS apt B and a proline hydroxylase ( apt A) that would catalyze one of the proline residues found in 1 – 6 to 4-hydroxyproline (Figure S17). , The module architecture of the apt B gene, one polyketide synthase (PKS) module followed by 16 NRPS modules, was similar to those reported for N -acetylated peptaibols. , The presence of the acyltransferase (AT) and ketosynthase (KS) domains in the loading PKS module agreed with the typical N-terminal acetylation of peptaibols. The thioesterase domain (TD) in the final module, which catalyzes the reduction of the C-terminal amino acid into its corresponding alcohol, was consistent with the C-terminal Pheol in 1 – 6 .…”

“…These results suggested that the Iva 12 residue was crucial for the antimicrobial activity, while conversion of Iva 4 to Aib 4 could significantly decrease the activity. Interestingly, the biological importance of the Iva residue in peptaibols was also observed with the 11-residue trichodermides A–E and the 15-residue pentadecaibins I–V assessed for cytotoxicities. The ascochlorin congeners 7 , 8 , and 10 showed potent antimicrobial activities against Gram-positive bacteria and/or C. albicans with MIC values of 1–32 μg/mL, whereas PF1171A was inactive (MIC > 128 μg/mL).…”

“…In the in vitro cytotoxicity assay against human cancer cell lines A549 (lung cancer) and HepG2 (hepatocellular carcinoma), compounds 1 – 6 did not exhibit any noticeable cytotoxicities (IC 50 ≥ 50 μM, Table S2) although many peptaibols were reported to show strong to moderate activities against a variety of human cancer cell lines. ,, The ascochlorin analogues 7 – 10 showed significant inhibitory activities against the A549 and/or HepG2 cancer cells with IC 50 values of 0.9–5.8 μM (Table S2); these results agreed with those reported previously …”

Rare Glutamic Acid Methyl Ester Peptaibols from Sepedonium ampullosporum Damon KSH 534 Exhibit Promising Antifungal and Anticancer Activity

“…The δ- methyl ester of glutamic acid is rarely recognized in natural peptaibols, with only five examples out of the over 1450 peptaibiotics reported in the literature so far [ 5 , 8 , 9 , 10 , 11 , 14 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. The first occurrence was reported for four peptaibols named Trichorzianines (TA) 1896, TA1924, TA1910, and TA1924a isolated from Trichoderma atroviride by Panizel et al in 2013 [ 13 ].…”

“…This class of compounds is defined as linear peptides with 5−20 amino acids (AA) residues including ( i ) a high proportion of the nonproteinogenic α,α-dialkylated amino acid α-aminoisobutyric acid (Aib); ( ii ) an N -acetyl terminus; ( iii ) and a C -terminal AA reduced into amino alcohol such as leucinol (Leuol) or phenylalaninol (Pheol) [ 1 ]. Peptaibols are intriguing not only because of the structural variability generated by varying amino acid building blocks, but also due to their broad range of bioactivities, i.e., cytotoxic [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], antibacterial [ 2 , 5 , 6 , 10 , 11 , 12 , 13 ], antiviral [ 14 , 15 ], antileishmanial [ 16 ], antifungal [ 5 , 6 , 17 , 18 , 19 ], plant root growth inhibiting [ 20 ], insecticidal [ 7 ], and anthelmintic activity [ 2 ]. Furthermore, ampullosporin A ( 3 ), a peptaibol isolated from Sepedonium ampullosporum Damon, has been shown to permit neuroleptic-like activity in mice [ 21 , 22 ], whereby it exhibited a more targeted interaction with the glutamatergic system, namely the N -methyl-D-aspartate (NMDA) receptor [ 23 ].…”