Colletodiol derivatives of the endophytic fungus Trichocladium sp.

The OSMAC (one strain many compounds) concept is a cultivation-based approach to increase the diversity of secondary metabolites in microorganisms. In this study, we applied the OSMAC-approach to the endophytic fungus Trichocladium sp. by supplementation of the cultivation medium with 2.5% phenylalanine. This experiment yielded five new compounds, trichocladiol (1), trichocladic acid (2), colletodiolic acid (3), colletolactone (4) and colletolic acid (5), together with five previously described ones (6-10). The structures were elucidated via comprehensive spectroscopic measurements, and the absolute configurations of compound 1 was elucidated by using TDDFT-ECD calculations. For formation of compounds 3-5, a pathway based on colletodiol biosynthesis is proposed. Compound 6 exhibited strong antibacterial activity against methicillin-resistant Staphylococcus aureus with a minimal inhibitory concentration (MIC) of 0.78 µM as well as a strong cytotoxic effect against the human monocytic cell line THP1 with an IC50 of 0.7 µM. Compound 8 showed moderate antibacterial activity against Mycobacterium tuberculosis with a MIC of 25 µM and a weak cytotoxic effect against THP1 cells with an IC50 of 42 µM.

3-O-Methyl-Alkylgallates Inhibit Fatty Acid Desaturation in Mycobacterium tuberculosis.

In the quest for new antibacterial lead structures, activity screening against Mycobacterium tuberculosis identified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoe Loranthus micranthus Structure-activity relationship studies indicated that 3-O-methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms showed the strongest growth inhibition in vitro against M. tuberculosis, with a MIC of 6.25 µM. Furthermore, the most active compounds (3-O-methyl-butyl-, 3-O-methyl-hexylgallate, and 3-O-methyl-octylgallate) were devoid of cytotoxicity against various human cell lines. Furthermore, 3-O-methyl-butylgallate showed favorable absorption, distribution, metabolism, and excretion (ADME) criteria, with a Papp of 6.2 × 10-6 cm/s, and it did not inhibit P-glycoprotein (P-gp), CYP1A2, CYP2B6 or CYP3A4. Whole-genome sequencing of spontaneous resistant mutants indicated that the compounds target the stearoyl-coenzyme A (stearoyl-CoA) delta-9 desaturase DesA3 and thereby inhibit oleic acid synthesis. Supplementation assays demonstrated that oleic acid addition to the culture medium antagonizes the inhibitory properties of gallic acid derivatives and that sodium salts of saturated palmitic and stearic acid did not show compensatory effects. The moderate bactericidal effect of 3-O-methyl-butylgallate in monotreatment was synergistically enhanced in combination treatment with isoniazid, leading to sterilization in liquid culture.

Metabolites from the endophytic fungus Cylindrocarpon sp. isolated from tropical plant Sapium ellipticum.

Three new polyketides, cylindrocarpones A-C (1-3), two new pyridone alkaloids, cylindrocarpyridones A-B (5-6), a new pyrone cylindropyrone (7), together with seven know compounds were isolated from the endophytic fungus, Cylindrocarpon sp., obtained from the tropical plant Sapium ellipticum. The structures of the new compounds were elucidated by extensive analysis of their spectroscopic data (1D and 2D NMR, HRESIMS). The absolute configuration of 19-O-methyl-pyrrocidine B (13) was confirmed by X-ray analysis. All isolated compounds were screened for their cytotoxic and antibacterial activities. Pyrrocidine A (12) exhibited potent cytotoxicity against the human ovarian cancer cell line A2780 with an IC50 value of 1.7 µM. 19-O-Methyl-pyrrocidine B (13) showed moderate antibacterial activity against S. aureus ATCC25923 and ATCC700699 with MIC values of 50 and 25 µM, respectively.