Center of Infectious Disease, West China Hospital, Sichuan University, Chengdu, China.
New Microbiol. 2023 Sep;46(3):285-295.
Antibiotic-resistant S. aureus infections can be life-threatening. Linezolid is known to hinder S. aureus biofilm formation, but the underlying molecular mechanism remains unclear. Molecular docking revealed that linezolid can bind to icaA, and this was confirmed by thermal drift assays. Linezolid demonstrated a dose-dependent inhibition of icaA enzyme activity. Mutating Trp267, a key residue identified through molecular docking, significantly decreased linezolid binding and inhibitory effects on mutant icaA activity. However, the mutant icaA Trp267Ala showed only slight activity reduction compared to icaA. Linezolid had minimal impact on icaB's thermal stability and activity. The 50S ribosomal L3ΔSer145 mutant S. aureus exhibited similar growth and biofilm formation to the wild-type strain. Linezolid effectively suppressed the growth and biofilm formation of wildtype S. aureus. Although linezolid lost its ability to inhibit the growth of the mutant strain, it still effectively hindered its biofilm formation. Linezolid exhibited weaker attenuation of sepsis-induced lung injury caused by 50S ribosomal L3ΔSer145 mutant S. aureus compared to wild-type S. aureus. These findings indicate that linezolid hampers S. aureus biofilm formation by directly inhibiting icaA activity, independently of its impact on bacterial growth.
耐抗生素金黄色葡萄球菌感染可能危及生命。已知利奈唑胺可抑制金黄色葡萄球菌生物膜形成，但潜在的分子机制尚不清楚。分子对接显示，利奈唑胺可以与 icaA 结合，这一点通过热漂移测定得到了证实。利奈唑胺表现出对 icaA 酶活性的剂量依赖性抑制作用。通过分子对接鉴定的关键残基色氨酸 267 的突变显著降低了利奈唑胺的结合和对突变 icaA 活性的抑制作用。然而，与 icaA 相比，突变体 icaA Trp267Ala 的活性仅略有降低。利奈唑胺对 icaB 的热稳定性和活性几乎没有影响。50S 核糖体 L3ΔSer145 突变金黄色葡萄球菌的生长和生物膜形成与野生型菌株相似。利奈唑胺有效抑制了野生型金黄色葡萄球菌的生长和生物膜形成。尽管利奈唑胺失去了抑制突变株生长的能力，但它仍然有效地阻止了其生物膜的形成。与野生型金黄色葡萄球菌相比，利奈唑胺对 50S 核糖体 L3ΔSer145 突变金黄色葡萄球菌引起的脓毒症诱导的肺损伤的减弱作用较弱。这些发现表明，利奈唑胺通过直接抑制 icaA 活性来阻碍金黄色葡萄球菌生物膜的形成，而不影响细菌的生长。
