Potentiating the activity of berberine for Staphylococcus aureus in a combinatorial treatment with thymol

Aksoy, Cemile Selin; Avcı, Fatma Gizem; Ugurel, Osman Mutluhan; Atas, Basak; Sayar, Adnan; Akbulut, Berna Sarıyar

doi:10.1016/j.micpath.2020.104542

Cited by 12 publications

(9 citation statements)

References 55 publications

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“…Berberine not only can exert an antimicrobial effect by regulating host immunity but also has a significant direct antimicrobial effect. Some experimental evidence shows that berberine alone or in combination with other agents showed obvious antimicrobial effects in vivo and in vitro (Aksoy et al, 2020 ; Huang et al, 2020 ; Xie et al, 2020 ; Bhatia et al, 2021 ). Berberine even has the potential to inhibit antibiotic-resistant bacteria (Morita et al, 2016 ; Zhang et al, 2020 ; Li et al, 2021 ), which gives it great potential in the development of new antibiotics.…”

Section: Introductionmentioning

confidence: 99%

A New Perspective on the Antimicrobial Mechanism of Berberine Hydrochloride Against Staphylococcus aureus Revealed by Untargeted Metabolomic Studies

Yang

Hong

et al. 2022

Front. Microbiol.

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Berberine hydrochloride (BBR) is a natural product widely used in clinical medicine and animal production. It has a variety of antimicrobial effects, but its complex antimicrobial mechanism has not been clarified. This study aimed to discover the metabolic markers and gain a new perspective on the antibacterial mechanism of BBR. The effects of different inhibitory concentrations of BBR on the survival and growth of standard strain Staphylococcus aureus ATCC 25923 were analyzed by the bacteriostatic activity test. Differences in intracellular metabolites of S. aureus following 19 μg/ml BBR exposure for 1 h were investigated by combining non-targeted metabolomics techniques of gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The results showed that the minimum inhibitory concentration of BBR against S. aureus was 51 μg/ml. A total of 368 and 3,454 putative metabolites were identified by GC-MS and LC-MS analyses, respectively. Principal component analysis showed the separation of intracellular metabolite profiles between BBR-exposed samples and non-exposed controls. Pathway activity profiling analysis indicated a global inhibition of metabolisms by BBR exposure, while enhancement was also found in nucleic acid metabolism, amino sugar, and nucleotide sugar metabolism. Several metabolic markers were screened out mainly based on their variable importance of projection values. Two pyridine dicarboxylic acids were significantly downregulated, suggesting the reduction of stress resistance. The oxidized phospholipid (PHOOA-PE) was accumulated, while lipid antioxidant gamma-tocopherol was decreased, and farnesyl PP, the synthetic precursor of another antioxidant (staphyloxanthin), was decreased below the detection threshold. This evidence indicates that BBR reduced the antioxidant capacity of S. aureus. Accumulation of the precursors (UDP-GlcNAc, CDP-ribitol, and CDP-glycerol) and downregulation of the key metabolite D-Ala-D-Ala suggest the inhibition of cell wall synthesis, especially the peptidoglycan synthesis. Metabolites involved in the shikimate pathway (such as 3-dehydroshikimate) and downstream aromatic amino acid synthesis were disturbed. This study provides the first metabolomics information on the antibacterial mechanism of BBR against S. aureus. The key metabolic markers screened in this study suggest that the shikimate pathway, staphyloxanthin synthesis, and peptidoglycan biosynthesis are new directions for further study of BBR antibacterial mechanism in the future.

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Section: Introductionmentioning

confidence: 99%

A New Perspective on the Antimicrobial Mechanism of Berberine Hydrochloride Against Staphylococcus aureus Revealed by Untargeted Metabolomic Studies

Yang

Hong

et al. 2022

Front. Microbiol.

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“…As demonstrated by several antibacterial investigations, BBR could inhibit the growth and reproduction of E. coli , S. aureus , etc [16] . And the antibacterial activity of BBR has been reported in multiple mechanisms: binding to DNA and RNA, inhibiting diverse enzymes, damaging biofilm formation, etc [17] . Considering the wide application of BBR, the regulation of its biological activity is of great significance to cope with the rising problems related to its large‐scale clinical administration.…”

Section: Introductionmentioning

confidence: 99%

A Supramolecular Antibiotic Switch for Plug‐and‐Play Antibacterial Regulation

Peng

Wang

et al. 2022

ChemNanoMat

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Constructing novel antibiotic switches is of great importance to fighting bacterial infections and reducing the public health threat caused by antibiotic abuse. In this work, a plug‐and‐play antibiotic switch based on the host‐guest interaction between berberine hydrochloride (BBR) and cucurbit[7]uril (CB[7]) is reported. BBR can be encapsulated in the cavity of CB[7] to form BBR@CB[7] with enhanced fluorescent emission and reduced antibacterial activity. And BBR can be released from BBR@CB[7] in the presence of other competitors, such as amantadine hydrochloride (ADA). The self‐assemble and disassemble ability of the supramolecular complex can be applied as facile plug‐and‐play antibiotic switch to “turn‐on” and “turn‐off” its antibacterial activity on demand. This work provides a simple, rapid, and efficient strategy for antibacterial regulation through supramolecular chemistry.

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“…Numerous natural compounds inhibiting virulence factor production of S. aureus , either alone or in combination with traditional antibiotics, have been reported [ 21 ]. For example, thymol (2-isopropyl-5-methylphenol), a constituent of thyme herb ( Thymus vulgaris L.), possesses a wide spectrum of antimicrobial activity [ 22 – 29 ] and reduces the biofilm formation of S. aureus strains [ 30 – 33 ]. Furthermore, it is known to inhibit staphyloxanthin production in MRSA [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Thymol Reduces agr-Mediated Virulence Factor Phenol-Soluble Modulin Production in Staphylococcus aureus

Lade

Kumbhar

Joo

et al. 2022

BioMed Research International

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Staphylococcus aureus is a major human bacterial pathogen that carries a large number of virulence factors. Many virulence factors of S. aureus are regulated by the accessory gene regulator (agr) quorum-sensing system. Phenol-soluble modulins (PSMs) are one of the agr-mediated virulence determinants known to play a significant role in S. aureus pathogenesis. In the present study, the efficacy of thymol to inhibit PSM production including δ-toxin in S. aureus was explored. We employed liquid chromatography–mass spectrometry (LC–MS) to quantify the PSMsα1–PSMα4, PSMβ1 and PSMβ2, and δ-toxin production from culture supernatants. We found that thymol at 0.5 MIC (128 μg/mL) significantly reduced the PSMα and δ-toxin production in S. aureus WKZ-1, WKZ-2, LAC USA300, and ATCC29213. Downregulation in transcription by quantitative real-time (qRT) PCR analysis of response regulator agrA and receptor histidine kinase agrC upon 0.5 MIC thymol treatment affirmed the results of LC–MS quantification of PSMs. In silico molecular docking analysis demonstrated the binding affinity of thymol with receptors AgrA and AgrC. Transmission electron microscopy images revealed no ultrastructural alterations (cell wall and membrane) in thymol-treated WKZ-1 and WKZ-2 S. aureus strains. Here, we demonstrated that thymol reduces various PSM production in S. aureus clinical isolates and reference strains with mass spectrometry.

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Potentiating the activity of berberine for Staphylococcus aureus in a combinatorial treatment with thymol

Cited by 12 publications

References 55 publications

A New Perspective on the Antimicrobial Mechanism of Berberine Hydrochloride Against Staphylococcus aureus Revealed by Untargeted Metabolomic Studies

A New Perspective on the Antimicrobial Mechanism of Berberine Hydrochloride Against Staphylococcus aureus Revealed by Untargeted Metabolomic Studies

A Supramolecular Antibiotic Switch for Plug‐and‐Play Antibacterial Regulation

Thymol Reduces agr-Mediated Virulence Factor Phenol-Soluble Modulin Production in Staphylococcus aureus

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