Department of Clinical Laboratory, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Clinical Laboratory, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 274 Zhijiang Middle Rd., Shanghai, 200071, China.
Appl Microbiol Biotechnol. 2024 Aug 5;108(1):432. doi: 10.1007/s00253-024-13268-2.
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.
金黄色葡萄球菌引起的感染是一个全球性的重大公共问题。因此，需要新的抗生素和治疗策略来对抗这种病原体。本研究深入探讨了新型叶酸合成抑制剂伊拉普里姆对金黄色葡萄球菌毒力的影响。我们全面研究了伊拉普里姆对金黄色葡萄球菌 MW2、N315 和 ATCC 25923 株的毒力因子、生物膜形成和分散以及与外蛋白、黏附和调节相关的部分毒力编码基因的表型和基因型影响。然后，我们通过大蜡螟幼虫感染模型探索了伊拉普里姆在金黄色葡萄球菌致病性中的体内有效性。在亚抑菌浓度（sub-MICs）下使用伊拉普里姆可减少α-溶血素（Hla）的产生，并对金黄色葡萄球菌株的凝固酶活性产生差异影响。生物膜形成和清除试验结果表明，伊拉普里姆在 1 MIC 或更高浓度下可有效解聚金黄色葡萄球菌株的成熟生物膜，但仅在 sub-MICs 下抑制 N315 和 ATCC 25923 株的生物膜形成能力。有趣的是，用 sub-MICs 的伊拉普里姆处理菌株可导致大多数毒力编码基因表达的显著刺激或抑制。伊拉普里姆不影响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。体内试验表明，sub-MICs 的伊拉普里姆可显著提高感染幼虫的存活率。本研究为更好地了解伊拉普里姆对不同金黄色葡萄球菌株的影响提供了有价值的见解。研究结果表明，伊拉普里姆可能具有作为抗毒力和抗生物膜剂的潜力，从而可能减轻金黄色葡萄球菌的致病性并改善与该病原体引起的感染相关的临床结果。
关键点：
伊拉普里姆以菌株依赖的方式有效抑制α-溶血素的产生和生物膜形成，是成熟生物膜的优秀解聚剂
伊拉普里姆影响与外蛋白、黏附和调节相关的毒力编码基因的 mRNA 表达
在金黄色葡萄球菌感染大蜡螟幼虫的体内研究中，伊拉普里姆可提高幼虫的存活率
