Flavonolignans from silymarin modulate antibiotic resistance and virulence in Staphylococcus aureus

Kateřina Holasová; Bára Křížkovská; Lan Hoang; Simona Dobiasová; Jan Lipov; Tomáš Macek; Vladimír Křen; Kateřina Valentová; Tomáš Ruml; Jitka Viktorová

doi:10.1016/j.biopha.2022.112806

Flavonolignans from silymarin modulate antibiotic resistance and virulence in Staphylococcus aureus

Biomed Pharmacother. 2022 May:149:112806. doi: 10.1016/j.biopha.2022.112806. Epub 2022 Mar 15.

Authors

Affiliations

¹ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: rehorova@vscht.cz.
² Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: krizkova@vscht.cz.
³ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: hoangl@vscht.cz.
⁴ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: dobiasos@vscht.cz.
⁵ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: lipovj@vscht.cz.
⁶ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: tomas.macek@vscht.cz.
⁷ Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech Republic. Electronic address: kren@biomed.cas.cz.
⁸ Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech Republic. Electronic address: kata.valentova@email.cz.
⁹ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: rumlt@vscht.cz.
¹⁰ Department of Biochemistry and Microbiology, Faculty of Food and Biochemical Technology, University of Chemistry and Technology, Prague, Technická 3, Prague 166 28, Czech Republic. Electronic address: prokesoj@vscht.cz.

PMID: 35303568
DOI: 10.1016/j.biopha.2022.112806

Abstract

Antibiotic resistance is currently a serious health problem. Since the discovery of new antibiotics no longer seems to be a sufficient tool in the fight against multidrug-resistant infections, adjuvant (combination) therapy is gaining in importance as well as reducing bacterial virulence. Silymarin is a complex of flavonoids and flavonolignans known for its broad spectrum of biological activities, including its ability to modulate drug resistance in cancer. This work aimed to test eleven, optically pure silymarin flavonolignans for their ability to reverse the multidrug resistance phenotype of Staphylococcus aureus and reduce its virulence. Silybin A, 2,3-dehydrosilybin B, and 2,3-dehydrosilybin AB completely reversed antibiotic resistance at concentrations of 20 µM or less. Both 2,3-dehydrosilybin B and AB decreased the antibiotic-induced gene expression of representative efflux pumps belonging to the major facilitator (MFS), multidrug and toxic compound extrusion (MATE), and ATP-binding cassette (ABC) families. 2,3-Dehydrosilybin B also inhibited ethidium bromide accumulation and efflux in a clinical isolate whose NorA and MdeA overproduction was induced by antibiotics. Most of the tested flavonolignans reduced cell-to-cell communication on a tetrahydrofuran-borate (autoinducer-2) basis, with isosilychristin leading the way followed by 2,3-dehydrosilybin A and AB, which halved communication at 10 µM. Anhydrosilychristin was the only compound that reduced communication based on acyl-homoserine lactone (autoinducer 1), with an IC₅₀ of 4.8 µM. Except for isosilychristin and anhydrosilychristin, all of the flavonolignans inhibited S. aureus surface colonization, with 2,3-dehydrosilybin A being the most active (IC₅₀ 10.6 µM). In conclusion, the selected flavonolignans, particularly derivatives of 2,3-dehydrosilybin B, 2,3-dehydrosilybin AB, and silybin A are non-toxic modulators of S. aureus multidrug resistance and can decrease the virulence of the bacterium, which deserves further detailed research.

Keywords: Efflux pump; Flavonolignans; Multidrug resistance; Silybin; Silychristin; Staphylococcus aureus.

MeSH terms

Anti-Bacterial Agents / pharmacology
Drug Resistance, Microbial
Humans
Silybin / pharmacology
Silymarin* / chemistry
Silymarin* / pharmacology
Staphylococcal Infections*
Staphylococcus aureus
Virulence

Substances

Anti-Bacterial Agents
Silymarin
Silybin