Elucidating the potential of isorhapontigenin in targeting the MgrA regulatory network: a paradigm shift for attenuating MRSA virulence.
Lihan LiuLi WangXiaolei LiuBingmei WangXuerui GuoYueying WangYueshan XuJiyu GuanYicheng ZhaoPublished in: Antimicrobial agents and chemotherapy (2024)
As methicillin-resistant Staphylococcus aureus (MRSA) exhibits formidable resistance to many drugs, the imperative for alternative therapeutic strategies becomes increasingly evident. At the heart of our study is the identification of a novel inhibitor through fluorescence anisotropy assays, specifically targeting the crucial multiple gene regulator A (MgrA) regulatory network in S. aureus . Isorhapontigenin (Iso), a natural compound, exhibits outstanding inhibitory efficacy, modulating bacterial virulence pathways without exerting direct bactericidal activity. This suggests a paradigm shift toward attenuating virulence instead of purely focusing on bacterial elimination. Through comprehensive in vitro and in vivo evaluations, we elucidated the complex interplay between Iso and MgrA, leading to reduced S. aureus adhesion, and overall virulence. At the cellular level, Iso offers significant protection to A549 cells infected with S. aureus , reducing cellular damage. Importantly, Iso augments the chemotaxis of neutrophils, curtailing the immune evasion capabilities of S. aureus . Furthermore, in vivo investigations highlight the notable effectiveness of Iso against MRSA-induced pneumonia and within the Galleria mellonella infection model, underscoring its pivotal role in the evolving realm of antibacterial drug discovery. Significantly, when Iso is used in combination with vancomycin, it outperforms its solo application, indicating a more pronounced therapeutic impact. This seminal research emphasizes Iso's potential as a primary defense against the surge of multidrug-resistant pathogens, heralding new prospects in antimicrobial therapy.
Keyphrases
- methicillin resistant staphylococcus aureus
- staphylococcus aureus
- biofilm formation
- escherichia coli
- pseudomonas aeruginosa
- antimicrobial resistance
- multidrug resistant
- drug discovery
- randomized controlled trial
- systematic review
- induced apoptosis
- cystic fibrosis
- cancer therapy
- signaling pathway
- gram negative
- atrial fibrillation
- high throughput
- single molecule
- drug resistant
- cell cycle arrest
- mesenchymal stem cells
- endoplasmic reticulum stress
- cell death
- acute respiratory distress syndrome
- high glucose
- current status
- drug delivery
- extracorporeal membrane oxygenation
- community acquired pneumonia
- genome wide identification
- climate change