Staphylococcus aureus is the major organism responsible for surgical implant infections. Antimicrobial treatment of these infections often fails, leading to expensive surgical intervention and increased risk of mortality to the patient. The challenge in treating these infections is associated with the high tolerance of S. aureus biofilm to antibiotics. MazEF, a toxin-antitoxin system, is thought to be an important regulator of this phenotype, but its physiological function in S. aureus is controversial. Here, we examined the role of MazEF in developing chronic infections by comparing growth and antibiotic tolerance phenotypes in three S. aureus strains to their corresponding strains with disruption of mazF expression. Strains lacking mazF production showed increased biofilm growth and decreased biofilm antibiotic tolerance. Deletion of icaADBC in the mazF::Tn background suppressed the growth phenotype observed with mazF-disrupted strains, suggesting the phenotype was ica dependent. We confirmed these phenotypes in our murine animal model. Loss of mazF resulted in increased bacterial burden and decreased survival rate of mice compared to its wild-type strain demonstrating that loss of the mazF gene caused an increase in S. aureus virulence. Although lack of mazF gene expression increased S. aureus virulence, it was more susceptible to antibiotics in vivo Combined, the ability of mazF to inhibit biofilm formation and promote biofilm antibiotic tolerance plays a critical role in transitioning from an acute to chronic infection that is difficult to eradicate with antibiotics alone.IMPORTANCE Surgical infections are one of the most common types of infections encountered in a hospital. Staphylococcus aureus is the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate, as the bacteria form biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria that are planktonic, bacteria in a biofilm are more resistant to antibiotics. The mechanism behind how bacteria develop this resistance and establish a chronic infection is unknown. We demonstrate that mazEF, a toxin-antitoxin gene, inhibits biofilm formation and promotes biofilm antibiotic tolerance which allows S. aureus to transition from an acute to chronic infection that cannot be eradicated with antibiotics but is less virulent. This gene not only makes the bacteria more tolerant to antibiotics but makes the bacteria more tolerant to the host.

中文翻译：

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毒素-抗毒素MazEF驱动金黄色葡萄球菌生物膜形成，抗生素耐受性和慢性感染。

金黄色葡萄球菌是引起外科植入物感染的主要生物。这些感染的抗微生物治疗通常失败，导致昂贵的外科手术干预并增加患者死亡的风险。治疗这些感染的挑战与金黄色葡萄球菌生物膜对抗生素的高耐受性有关。MazEF是一种毒素-抗毒素系统，被认为是该表型的重要调节剂，但其在金黄色葡萄球菌中的生理功能尚有争议。在这里，我们通过比较三种金黄色葡萄球菌菌株及其对应菌株的mazF表达破坏，比较了其生长和抗生素耐受表型，从而研究了MazEF在发展慢性感染中的作用。缺乏mazF产生的菌株显示出生物膜生长增加和生物膜抗生素耐受性降低。在mazF :: Tn背景中删除icaADBC抑制了mazF干扰菌株观察到的生长表型，表明该表型是ica依赖性的。我们在鼠类动物模型中证实了这些表型。与野生型菌株相比，mazF的缺失导致小鼠细菌负担增加，存活率降低，这表明mazF基因的缺失导致金黄色葡萄球菌毒力增加。尽管缺乏mazF基因表达会增加金黄色葡萄球菌的毒力，但它在体内更容易受到抗生素的综合影响，mazF抑制生物膜形成和促进生物膜抗生素耐受性的能力在从急性感染向慢性感染的转化中起着关键作用单独使用抗生素即可根除。重要信息外科感染是医院中最常见的感染类型之一。金黄色葡萄球菌是与此感染相关的最常见病原体。当细菌形成生物膜时，这些感染是有弹性的，并且难以根除，是由细胞外基质结合在一起的细菌群落。与浮游细菌相比，生物膜中的细菌对抗生素更具抵抗力。细菌如何产生这种抗性并建立慢性感染的机制尚不清楚。我们证明，mazEF，一种毒素-抗毒素基因，抑制生物膜形成并促进生物膜抗生素耐受性，使金黄色葡萄球菌从急性感染转变为无法用抗生素消除但毒性较低的慢性感染。