Refine
Year of publication
- 2022 (2) (remove)
Document Type
- Article (2)
Language
- English (2)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- - (1)
- Bakterien (1)
- COVID-19 (1)
- Extrakt (1)
- Gerbstoff (1)
- SARS-CoV-2 (1)
- deubiquitination (1)
- drug discovery (1)
- lead compounds (1)
- papain-like protease (1)
- tannins and flavonoids; anti-biofilm; E. coli; Epilobium; Filipendula; R. chamaemorus; biological activities; ethnobotany (1)
- x-ray crystallography (1)
Institute
Publisher
- Frontiers Media S.A. (1)
- MDPI (1)
In the search for alternative treatment options for infections with multi-resistant germs,
traditionally used medicinal plants are currently being examined more intensively. In this study,
the antimicrobial and anti-biofilm activities of 14 herbal drugs were investigated. Nine of the tested
drugs were traditionally used in Europe for treatment of local infections. For comparison, another
five drugs monographed in the European Pharmacopoeia were used. Additionally, the total tannin
and flavonoid contents of all tested drugs were analyzed. HPLC fingerprints were recorded to ob-
tain further insights into the components of the extracts. The aim of the study was to identify herbal
drugs that might be useable for treatment of infectious diseases, even with multidrug resistant E.
coli, and to correlate the antimicrobial activity with the total content of tannins and flavonoids. The
agar diffusion test and anti-biofilm assay were used to evaluate the antimicrobial potential of dif-
ferent extracts from the plants. Colorimetric methods (from European Pharmacopeia) were used for
determination of total tannins and flavonoids. The direct antimicrobial activity of most of the tested
extracts was low to moderate. The anti-biofilm activity was found to be down to 10 µg mL −1 for
some extracts. Tannin contents between 2.2% and 10.4% of dry weight and total flavonoid contents
between 0.1% and 1.6% were found. Correlation analysis indicates that the antimicrobial and the
anti-biofilm activity is significantly (p < 0.05) dependent on tannin content, but not on flavonoid
content. The data analysis revealed that tannin-rich herbal drugs inhibit pathogens in different
ways. Thus, some of the tested herbal drugs might be useable for local infections with multi-re-
sistant biofilm-forming pathogens. For some of the tested drugs, this is the first report about anti-
biofilm activity, as well as total tannin and flavonoid content.
The papain-like protease (PLpro) of SARS-CoV-2 is essential for viral propagation and, additionally, dysregulation of the host innate immune system. Using a library of 40 potential metal-chelating compounds we performed an X-ray crystallographic screening against PLpro. As outcome we identified six compounds binding to the target protein. Here we describe the interaction of one hydrazone (H1) and five thiosemicarbazone (T1-T5) compounds with the two distinct natural substrate binding sites of PLpro for ubiquitin and ISG15. H1 binds to a polar groove at the S1 binding site by forming several hydrogen bonds with PLpro. T1-T5 bind into a deep pocket close to the polyubiquitin and ISG15 binding site S2. Their interactions are mainly mediated by multiple hydrogen bonds and further hydrophobic interactions. In particular compound H1 interferes with natural substrate binding by sterical hindrance and induces conformational changes in protein residues involved in substrate binding, while compounds T1-T5 could have a more indirect effect. Fluorescence based enzyme activity assay and complementary thermal stability analysis reveal only weak inhibition properties in the high micromolar range thereby indicating the need for compound optimization. Nevertheless, the unique binding properties involving strong hydrogen bonding and the various options for structural optimization make the compounds ideal lead structures. In combination with the inexpensive and undemanding synthesis, the reported hydrazone and thiosemicarbazones represent an attractive scaffold for further structure-based development of novel PLpro inhibitors by interrupting protein-protein interactions at the S1 and S2 site.