Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of α-hemolysin

Zhang, Hong; Jiang, Jizong; Han, Li; Lao, Yuanzhi; Zheng, Dan; Chen, Yuyu; Wan, Shi-Jie; Zheng, Changwu; Tan, Hongsheng; Li, Zi-Gang; Hong, Xu

doi:10.1016/j.phrs.2019.104328

Cited by 7 publications

(3 citation statements)

References 49 publications

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“…The experiments were performed according to our previous study ( Zhang H et al, 2019 ). The overnight liquid cultures of S. aureus were diluted 20-fold in fresh TSB in a 50 mL flask and then cultured at 37°C for approximately 3 h to an OD 600 of 0.6.…”

Section: Methodsmentioning

confidence: 99%

Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus

et al. 2022

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The emergence of antibiotic resistance in Staphylococcus aureus has necessitated the development of innovative anti-infective agents acting on novel targets. Alpha-hemolysin (Hla), a key virulence factor of S. aureus, is known to cause various cell damage and death. In this study, with bioassay-guided fractionation, a pair of unusual epimeric lignan trimers, ligustchuanes A and B (1 and 2), were isolated from the rhizomes of Ligusticum chuanxiong Hort, together with two known phthalides being identified by UPLC-QTOF-MS. To the best of our knowledge, trimers with rare C8-C9″-type neolignan and ferulic acid fragments have not been identified in any natural product. Both of them were isolated as racemic mixtures, and their absolute configurations were determined by comparing experimental and calculated ECD spectra after enantioseparation. Ligustchuane B exhibited an outstanding inhibitory effect on α-hemolysin expression in both MRSA USA300 LAC and MSSA Newman strains at concentrations of 3 and 6 μM, respectively. Notably, a mouse model of infection further demonstrated that ligustchuane B could attenuate MRSA virulence in vivo.

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Section: Methodsmentioning

confidence: 99%

Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus

et al. 2022

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“…In addition to the action of RNAIII, MgrA biosynthesis is subject to regulation by another small RNA-mediated mechanism 12 . Mutations or inhibition of the mgrA gene within S. aureus diminish virulence, thus highlighting its promising potential as a target for novel antivirulence therapies 13 , 14 . Developing MgrA-specific inhibitors could pave the way for novel therapeutic strategies to combat recalcitrant S. aureus infections.…”

Section: Introductionmentioning

confidence: 99%

Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus

Guo,

Wang,

Zhang

et al. 2024

npj Biofilms Microbiomes

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Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets—becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.

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“…Compounds extracted from medicinal plants are a rich source of unique phytochemicals, as many novel bioactive products from traditional Chinese medicine have been shown to display significant anti-virulence activity [ 21 - 23 ]. Isovitexin (apigenin-6-C-β-glucopyranoside) ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Isovitexin Is a Direct Inhibitor of Staphylococcus aureus Coagulase

Xiang

Yang

Wang

et al. 2021

J. Microbiol. Biotechnol.

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Staphylococcus aureus (S. aureus) is a major pathogen that causes human pneumonia, leading to significant morbidity and mortality. S. aureus coagulase (Coa) triggers the polymerization of fibrin by activating host prothrombin, which then converts fibrinogen to fibrin and contributes to S. aureus pathogenesis and persistent infection. In our research, we demonstrate that isovitexin, an active traditional Chinese medicine component, can inhibit the coagulase activity of Coa but does not interfere with the growth of S. aureus. Furthermore, we show through thermal shift and fluorescence quenching assays that isovitexin directly binds to Coa. Dynamic simulation and structure-activity relationship analyses suggest that V191 and P268 are key amino acid residues responsible for the binding of isovitexin to Coa. Taken together, these data indicate that isovitexin is a direct Coa inhibitor and a promising candidate for drug development against S. aureus infection.

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Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of α-hemolysin

Cited by 7 publications

References 49 publications

Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus

Two Novel Phenylpropanoid Trimers From Ligusticum chuanxiong Hort With Inhibitory Activities on Alpha-Hemolysin Secreted by Staphylococcus aureus

Thwarting resistance: MgrA inhibition with methylophiopogonanone a unveils a new battlefront against S. aureus

Isovitexin Is a Direct Inhibitor of Staphylococcus aureus Coagulase

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