Xanthoepocin

Xanthoepocin

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Category Antibiotics
Catalog number BBF-02977
CAS
Molecular Weight 606.49
Molecular Formula C30H22O14

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Description

It is produced by the strain of Penicillum simplicissimum IFO5762. It has anti-gram-positive bacteria activity, it can inhibit Bacillus subtilis and methicillin-resistant Staphylococcus aureus (MRSA) with MIC of 0.78-1.56 μg/mL. It also has anti-yeast-like fungal activity, and it can inhibit Saccharomyces cerevisiae, Candida albicans and Cryptococcus neoformans with MIC of 3.13-25 μg/mL. It also has weak cytotoxicity to U937 cells with IC50 of 35 μg/mL.

Specification

Synonyms 2,2',3,3'-Tetrahydroxy-9a,9a'-dimethoxy-6,6'-dimethyl-2H,2'H,4H,4'H-1a,1a'-bi[1]benzoxireno[3,4-g]isochromene-4,4',9,9'(9aH,9a'H)-tetrone; [1a,1'a(4H,4'H)-Bi-2H-oxireno[6,7]naphtho[2,3-c]pyran]-4,4',9,9'(9aH,9a'H)-tetrone, 2,2',3,3'-tetrahydroxy-9a,9'a-dimethoxy-6,6'-dimethyl-
IUPAC Name 14-(2,15-dihydroxy-12-methoxy-6-methyl-4,11-dioxo-5,13-dioxatetracyclo[8.5.0.03,8.012,14]pentadeca-1(10),2,6,8-tetraen-14-yl)-2,15-dihydroxy-12-methoxy-6-methyl-5,13-dioxatetracyclo[8.5.0.03,8.012,14]pentadeca-1(10),2,6,8-tetraene-4,11-dione
Canonical SMILES CC1=CC2=CC3=C(C(C4(C(C3=O)(O4)OC)C56C(C7=C(C=C8C=C(OC(=O)C8=C7O)C)C(=O)C5(O6)OC)O)O)C(=C2C(=O)O1)O
InChI InChI=1S/C30H22O14/c1-9-5-11-7-13-17(19(31)15(11)25(37)41-9)23(35)27(29(39-3,43-27)21(13)33)28-24(36)18-14(22(34)30(28,40-4)44-28)8-12-6-10(2)42-26(38)16(12)20(18)32/h5-8,23-24,31-32,35-36H,1-4H3
InChI Key KJPAOKCLRDGPMI-UHFFFAOYSA-N

Properties

Appearance Yellow Powder
Antibiotic Activity Spectrum Gram-positive bacteria; Fungi; Yeast
Boiling Point 874.7±65.0°C at 760 mmHg
Melting Point >180°C (dec.)
Density 1.9±0.1 g/cm3
Solubility Soluble in Pyridine, Methanol

Reference Reading

1. Xanthoepocin, a photolabile antibiotic of Penicillium ochrochloron CBS 123823 with high activity against multiresistant gram-positive bacteria
Pamela Vrabl, Bianka Siewert, Jacqueline Winkler, Harald Schöbel, Christoph W Schinagl, Ludwig Knabl, Dorothea Orth-Höller, Johannes Fiala, Michael S Meijer, Sylvestre Bonnet, Wolfgang Burgstaller Microb Cell Fact. 2022 Jan 4;21(1):1. doi: 10.1186/s12934-021-01718-9.
Background: With the steady increase of antibiotic resistance, several strategies have been proposed in the scientific community to overcome the crisis. One of many successful strategies is the re-evaluation of known compounds, which have been early discarded out of the pipeline, with state-of-the-art know-how. Xanthoepocin, a polyketide widespread among the genus Penicillium with an interesting bioactivity spectrum against gram-positive bacteria, is such a discarded antibiotic. The purpose of this work was to (i) isolate larger quantities of this metabolite and chemically re-evaluate it with modern technology, (ii) to explore which factors lead to xanthoepocin biosynthesis in P. ochrochloron, and (iii) to test if it is beside its known activity against methicillin-resistant Staphylococcus aureus (MRSA), also active against linezolid and vancomycin-resistant Enterococcus faecium (LVRE)-a very problematic resistant bacterium which is currently on the rise. Results: In this work, we developed several new protocols to isolate, extract, and quantify xanthoepocin out of bioreactor batch and petri dish-grown mycelium of P. ochrochloron. The (photo)chemical re-evaluation with state-of-the-art techniques revealed that xanthoepocin is a photolabile molecule, which produces singlet oxygen under blue light irradiation. The intracellular xanthoepocin content, which was highest under ammonium-limited conditions, varied considerably with the applied irradiation conditions in petri dish and bioreactor batch cultures. Using light-protecting measures, we achieved MIC values against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which were up to 5 times lower than previously published. In addition, xanthoepocin was highly active against a clinical isolate of linezolid and vancomycin-resistant Enterococcus faecium (LVRE). Conclusions: This interdisciplinary work underlines that the re-evaluation of known compounds with state-of-the-art techniques is an important strategy in the combat against multiresistant bacteria and that light is a crucial factor on many levels that needs to receive more attention. With appropriate light protecting measures in the susceptibility tests, xanthoepocin proved to be a powerful antibiotic against MRSA and LVRE. Exploring the light response of other polyketides may be pivotal for re-introducing previously discarded metabolites into the antibiotic pipeline and to identify photosensitizers which might be used for (antimicrobial) photodynamic therapies.
2. Diversity in Fungal Intermolecular Phenol Coupling of Polyketides: Regioselective Laccase-Based Systems
Leon Fürtges, Sebastian Obermaier, Wiebke Thiele, Silke Foegen, Michael Müller Chembiochem. 2019 Aug 1;20(15):1928-1932. doi: 10.1002/cbic.201900041. Epub 2019 Jul 8.
Polyketides form a structurally diverse and pharmaceutically important class of secondary metabolites. Both diversity and biological activity are largely facilitated by post-polyketide synthase tailoring including methylation, oxidation, reduction, glycosylation, and dimerization. Cytochrome P450 enzymes (CYPs), flavin-dependent monooxygenases (FMOs), and laccases are known to catalyze phenol coupling in the biosynthesis of polyketide dimers. Polyketide homodimers resulting from enzyme catalysis are often formed in a highly regio- and stereoselective manner, in contrast to analogous nonenzymatic dimerization. Although it is known that CYPs and FMOs are capable of selectively generating one of several putative isomers, hitherto described laccases depend on auxiliary proteins to achieve similar selectivity. Herein, regioselective phenol coupling catalyzed by a fungal laccase is demonstrated. The heterologously produced Av-VirL from Aspergillus viridinutans selectively generated the 6,6'-homodimer of (R)-semivioxanthin. Genome analysis is used to show that laccase-based phenol-coupling systems are widespread in fungi. Homologues of Av-VirL were identified in the putative biosynthetic gene clusters of vioxanthin, xanthomegnin, and xanthoepocin, and of the perylenequinones hypocrellin A, elsinochrome A, and cercosporin. These findings show that laccases are capable of selective phenol coupling in the absence of auxiliary proteins.
3. Absolute configuration and protein tyrosine phosphatase 1B inhibitory activity of xanthoepocin, a dimeric naphtopyrone from Penicillium sp. IQ-429
Ingrid Y Martínez-Aldino, Martha Villaseca-Murillo, Jesús Morales-Jiménez, José Rivera-Chávez Bioorg Chem. 2021 Oct;115:105166. doi: 10.1016/j.bioorg.2021.105166. Epub 2021 Jul 15.
Protein tyrosine phosphatase 1B (PTP1B) is an active target for developing drugs to treat type II diabetes, obesity, and cancer. However, in the past, research programs targeting this enzyme focused on discovering inhibitors of truncated models (hPTP1B1-282, hPTP1B1-298, or hPTP1B1-321), losing valuable information about the ligands' mechanism of inhibition and selectivity. Nevertheless, finding an allosteric site in hPTP1B1-321, and the full-length (hPTP1B1-400) protein expression, have shifted the strategies to discover new PTP1B inhibitors. Accordingly, as part of a research program directed at finding non-competitive inhibitors of hPTP1B1-400 from Pezizomycotina, the extract of Penicillium sp. (IQ-429) was chemically investigated. This study led to xanthoepocin (1) isolation, which was elucidated by means of spectroscopic and spectrometric data. The absolute configuration of 1 was determined to be 7R8S9R7'R8'S9'R by comparing the theoretical and experimental ECD spectra and by GIAO-NMR DP4 + statistical analysis. Xanthoepocin (1) inhibited the phosphatase activity of hPTP1B1-400 (IC50 value of 8.8 ± 1.0 µM) in a mixed type fashion, with ki and αki values of 5.5 and 6.6 μM, respectively. Docking xanthoepocin (1) with a homologated model of hPTP1B1-400 indicated that it binds in a pocket different from the catalytic triad at the interface of the N and C-terminal domains. Molecular dynamics (MD) simulations showed that 1 locks the WPD loop of hPTP1B1-400 in a closed conformation, avoiding substrate binding, products release, and catalysis, suggesting an allosteric modulation triggered by large-scale conformational and dynamics changes. Intrinsic quenching fluorescence experiments indicated that 1 behaves like a static quencher of hPTP1B1-400 (KSV = 1.1 × 105 M-1), and corroborated that it binds to the enzyme with an affinity constant (ka) of 3.7 × 105 M-1. Finally, the drug-likeness and medicinal chemistry friendliness of 1 were predicted with SwissADME.

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