Abstract:Abscisic acid (ABA) plays an important role in the response of plants to drought stress. However, the chemical structure of ABA is unstable, which severely limits its application in agricultural production. Here, we report the identification of a small molecule compound of tetrazolium as an ABA analog (named SLG1) through virtual screening. SLG1 inhibits the seedling growth and promotes drought resistance of Arabidopsis thaliana with higher stability. Yeast two-hybrid and PP2C inhibition assays show that SLG1 … Show more
“…Of the CDOCKER scores obtained, eight exhibited absolute values greater than 100 (Dataset 2). These thresholds were established to ensure a high likelihood of significant binding while maintaining a manageable number of lead compounds for further evaluation 20 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…In determining the final dosage of the mortality study, we integrated previous research with the findings from our preliminary experiments, which are presented in Supplementary Fig. 9 20 , 26 . Without Mo-A treatment, the survival rate was merely 20% within 96 h post-infection; however, treatment with a combination of Mo-A and vancomycin markedly increased this rate to 70% (Fig.…”
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.
“…Of the CDOCKER scores obtained, eight exhibited absolute values greater than 100 (Dataset 2). These thresholds were established to ensure a high likelihood of significant binding while maintaining a manageable number of lead compounds for further evaluation 20 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…In determining the final dosage of the mortality study, we integrated previous research with the findings from our preliminary experiments, which are presented in Supplementary Fig. 9 20 , 26 . Without Mo-A treatment, the survival rate was merely 20% within 96 h post-infection; however, treatment with a combination of Mo-A and vancomycin markedly increased this rate to 70% (Fig.…”
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.
“…Notably, the crystal structure of Arabidopsis PYL2 (AtPYL2) protein and its ligand-binding pocket to ABA have been resolved ( 22 , 25 , 60 ). The specificity of PYL2 for ABA recognition is mainly due to two charge-stabilized hydrogen bonds between the carboxylate of ABA and Lys-64 of PYL2 ( 25 , 60 ), which are consistent with our predicted ligand-binding pockets ( Fig. 1 ).…”
Section: Discussionmentioning
confidence: 99%
“…1 ). It is previously reported that ABA directly binds AtPYL2 by the sites of Lys-64, Phe-66, Val-87, Ala-93, His-119, Leu-121, Tyr-124, Val-166, and Val-169 ( 60 ), which are similar to the ABA-binding pocket of FaPYL2, including Lys-70, Ile-73, Val-92, Ala-98, Ser-101, Glu-103, Ser-131, Glu-150, Val-172, Ile-173, and Asn-176 ( Fig. S4 ).…”
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
