由于耐甲氧西林金黄色葡萄球菌(MRSA)对许多药物表现出强大的耐药性,替代治疗策略的必要性变得越来越明显.我们研究的核心是通过荧光各向异性测定鉴定一种新型抑制剂,特异性靶向金黄色葡萄球菌中关键的多基因调节因子A(MgrA)调节网络。Isorhapontigenin(Iso),一种天然化合物,表现出突出的抑制功效,调节细菌毒力途径而不发挥直接杀菌活性。这表明范式转向减弱毒力,而不是纯粹专注于细菌消除。通过全面的体外和体内评估,我们阐明了Iso和Mcra之间复杂的相互作用,导致金黄色葡萄球菌粘附减少,和整体毒力。在细胞层面,Iso为感染金黄色葡萄球菌的A549细胞提供了显着的保护,减少细胞损伤。重要的是,Iso增强了中性粒细胞的趋化性,降低金黄色葡萄球菌的免疫逃避能力。此外,体内研究强调了Iso对MRSA引起的肺炎和GalleriaMellonella感染模型的显着有效性,强调其在不断发展的抗菌药物发现领域的关键作用。重要的是,当Iso与万古霉素联合使用时,它优于其单独应用程序,表明更明显的治疗效果。这项开创性的研究强调了Iso作为对抗多药耐药病原体激增的主要防御手段的潜力,预示着抗菌治疗的新前景。
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.