Abstract：
The increasing prevalence of infections related to methicillin-resistant Staphylococcus aureus (MRSA) necessitates the exploration of innovative therapeutic strategies that diverge from conventional antibiotic treatments. This is imperative to effectively combat resistance and manage these infections. The adoption of antivirulence strategies has emerged as a particularly promising avenue. This approach applies a heightened selective pressure on pathogens, thereby diminishing the likelihood of bacteria evolving resistance to antibiotics. In our pursuit of novel therapeutics for treating MRSA infections, we have focused on agents that inhibit the virulence of S. aureus without impeding its growth, aiming to minimize the development of drug resistance. α-Hemolysin, a critical virulence factor encoded by the hla gene, is a cytotoxin that forms pores in host cell membranes and plays a pivotal role in the progression of disease during bacterial infections. Herein, we identified that norwogonin could effectively inhibit Hla production via targeting agrAC, a crucial protein in quorum sensing, resulting in dose-dependent inhibition of hemolytic activity without suppressing S. aureus growth. In vitro assays illustrated that norwogonin decreased the thermal stability of agrAC, providing evidence of interaction between norwogonin and agrAC. Meanwhile, norwogonin alleviated Hla-mediated A549 cell damage and reduced lactate dehydrogenase release. In vivo studies suggested that norwogonin treatment blocked the establishment of a mouse model of pneumonia caused by S. aureus USA300. Notably, norwogonin enhanced the antibacterial potency of oxacillin. In conclusion, norwogonin is a promising candidate for treating S. aureus infections, offering a novel alternative to traditional antibiotics by targeting virulence factors and enhancing the efficacy of existing treatments.
摘要：
与耐甲氧西林金黄色葡萄球菌（MRSA）相关的感染患病率增加，需要探索与传统抗生素治疗不同的创新治疗策略。这对于有效对抗耐药性和管理这些感染至关重要。采用抗毒力策略已成为特别有希望的途径。这种方法对病原体施加了更高的选择压力，从而降低细菌对抗生素产生耐药性的可能性。在我们寻求治疗MRSA感染的新疗法的过程中，我们专注于抑制金黄色葡萄球菌毒力而不阻碍其生长的药物，旨在尽量减少耐药性的发展。α-溶血素,由hla基因编码的关键毒力因子，是一种在宿主细胞膜上形成孔的细胞毒素，在细菌感染期间的疾病进展中起关键作用。在这里，我们发现诺沃金可以通过靶向agrAC有效抑制Hla的产生，群体感应中的一种关键蛋白质，导致溶血活性的剂量依赖性抑制而不抑制金黄色葡萄球菌的生长。体外实验表明，诺维金降低了agrAC的热稳定性，提供诺沃金宁和agrAC相互作用的证据。同时,去甲Wogonin减轻了Hla介导的A549细胞损伤并减少了乳酸脱氢酶的释放。体内研究表明，去甲肾上腺素治疗阻止了金黄色葡萄球菌USA300引起的肺炎小鼠模型的建立。值得注意的是,诺维甲素增强了苯唑西林的抗菌效力。总之,norwogonin是治疗金黄色葡萄球菌感染的有希望的候选人，通过靶向毒力因子和增强现有治疗的疗效，为传统抗生素提供了一种新的替代品。
