抽象的
金黄色葡萄球菌引起的感染构成了一个重大的全球公共问题。因此，需要新的抗生素和治疗策略来对抗这种病原体。这项研究深入探讨了 iclaprim（一种新发现的叶酸合成抑制剂）对金黄色葡萄球菌的影响。金黄色葡萄球菌毒力。彻底检查了iclaprim的表型和基因型效应与毒力因子、生物膜形成和扩散的关系，以及与链球菌中的外蛋白、粘附和调节相关的部分毒力编码基因。金黄色葡萄球菌MW2、N315 和 ATCC 25923。然后，iclaprim 对金黄色葡萄球菌的体内有效性。通过大蜡螟幼虫感染模型探讨了金黄色葡萄球菌的致病性。使用亚抑制浓度（亚 MIC）的艾克拉普林会导致 α-溶血素 (Hla) 产生减少，并对沙门氏菌中凝固酶的活性产生不同的影响。金黄色葡萄球菌菌株。生物膜形成和根除试验结果表明，iclaprim 对金黄色葡萄球菌成熟生物膜的解聚非常有效。然而，浓度为 1 MIC 或更高的金黄色葡萄球菌菌株仅抑制亚 MIC 菌株 N315 和 ATCC 25923 的生物膜形成能力。有趣的是，用 Iclaprim 的亚 MIC 处理菌株会显着刺激或抑制大多数毒力编码基因的表达。 Iclaprim 不影响 δ-溶血素或葡萄球菌蛋白 A (SpA) 的产生，也不影响蛋白酶、核酸酶和脂肪酶的总活性。 体内测试表明 iclaprim 的亚 MIC 显着提高了受感染幼虫的存活率。本研究为更好地了解 iclaprim 对不同金黄色葡萄球菌菌株的影响提供了宝贵的见解。研究结果表明，iclaprim 可能具有作为抗毒力和抗生物膜剂的潜力，从而有可能减轻金黄色葡萄球菌的致病性。金黄色葡萄球菌并改善与该病原体引起的感染相关的临床结果。
要点
• Iclaprim 以菌株依赖性方式有效抑制 α-溶血素产生和生物膜形成，是成熟生物膜的优异解聚剂
• Iclaprim 影响与外蛋白、粘附和调节相关的毒力编码基因的 mRNA 表达
•用金黄色葡萄球菌攻击的大蜡螟幼虫的体内研究表明，iclaprim 可提高幼虫的存活率
"点击查看英文标题和摘要"
Anti-virulence potential of iclaprim, a novel folic acid synthesis inhibitor, against Staphylococcus aureus
Abstract
Infections caused by Staphylococcus aureus pose a significant global public problem. Therefore, new antibiotics and therapeutic strategies are needed to combat this pathogen. This investigation delves into the effects of iclaprim, a newly discovered inhibitor of folic acid synthesis, on S. aureus virulence. The phenotypic and genotypic effects of iclaprim were thoroughly examined in relation to virulence factors, biofilm formation, and dispersal, as well as partial virulence-encoding genes associated with exoproteins, adherence, and regulation in S. aureus MW2, N315, and ATCC 25923. Then, the in vivo effectiveness of iclaprim on S. aureus pathogenicity was explored by a Galleria mellonella larvae infection model. The use of iclaprim at sub-inhibitory concentrations (sub-MICs) resulted in a reduction of α-hemolysin (Hla) production and a differential effect on the activity of coagulase in S. aureus strains. The results of biofilm formation and eradication assay showed that iclaprim was highly effective in depolymerizing the mature biofilm of S. aureus strains at concentrations of 1 MIC or greater, however, inhibited the biofilm-forming ability of only strains N315 and ATCC 25923 at sub-MICs. Interestingly, treatment of strains with sub-MICs of iclaprim resulted in significant stimulation or suppression of most virulence-encoding genes expression. Iclaprim did not affect the production of δ-hemolysin or staphylococcal protein A (SpA), nor did it impact the total activity of proteases, nucleases, and lipases. In vivo testing showed that sub-MICs of iclaprim significantly improves infected larvae survival. The present study offered valuable insights towards a better understating of the influence of iclaprim on different strains of S. aureus. The findings suggest that iclaprim may have potential as an anti-virulence and antibiofilm agent, thus potentially mitigating the pathogenicity of S. aureus and improving clinical outcomes associated with infections caused by this pathogen.
Key points
• Iclaprim effectively inhibits α-hemolysin production and biofilm formation in a strain-dependent manner and was an excellent depolymerizing agent of mature biofilm
• Iclaprim affected the mRNA expression of virulence-encoding genes associated with exoproteins, adherence, and regulation
• In vivo study in G. mellonella larvae challenged with S. aureus exhibited that iclaprim improves larvae survival
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