Abstract

In the search for new microbial antibacterial secondary metabolites, two new compounds (1 and 2) were isolated from culture broths of Penicillium spathulatum Em19. Structure determination by nuclear magnetic resonance and mass spectrometry identified the compounds as 6,7-dihydroxy-5,10-dihydropyrrolo[1,2-b]isoquinoline-3-carboxylic acid (1, spathullin A) and 5,10-dihydropyrrolo[1,2-b]isoquinoline-6,7-diol (2, spathullin B). The two compounds displayed activity against both Gram-negative and -positive bacteria, including Escherichia coli, Acinetobacterbaumannii, Enterobactercloacae, Klebsiellapneumonia, Pseudomonasaeruginosa, and Staphylococcusaureus. Compound 2 was more potent than 1 against all tested pathogens, with minimal inhibitory concentrations down to 1 mu g/mL (5 mu M) against S. aureus, but 2 was also more cytotoxic than 1 (50% inhibitory concentrations 112 and 11 mu M for compounds 1 and 2, respectively, towards Huh7 cells). Based on stable isotope labelling experiments and a literature comparison, the biosynthesis of 1 was suggested to proceed from cysteine, tyrosine and methionine via a non-ribosomal peptides synthase like enzyme complex, whereas compound 2 was formed spontaneously from 1 by decarboxylation. Compound 1 was also easily oxidized to the 1,2-benzoquinone 3. Due to the instability of compound 1 and the toxicity of 2, the compounds are of low interest as possible future antibacterial drugs.

Keywords

antibiotic resistance; antibacterial secondary metabolites; secondary metabolism; Penicillium; isoquinoline alkaloids; dehydroalanine

Published in

Molecules
2019, volume: 24, number: 24, article number: 4616

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