The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
The Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic Infection
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DOI：
10.1128/mbio.01658-19
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发表时间：
2019-11-01
期刊：
影响因子：
6.4
通讯作者：
Urish, Kenneth L.
中科院分区：
文献类型：
--
作者：
Ma, Dongzhu;Mandell, Jonathan B.;Urish, Kenneth L.
金黄色葡萄球菌是外科植入物感染的主要病原菌。这些感染的抗菌治疗往往失败，导致昂贵的手术干预和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，被认为是这种表型的重要调节因子，但其在金黄色葡萄球菌中的生理功能存在争议。在这里，我们通过比较三种金黄色葡萄球菌菌株的生长和抗生素耐受性表型，研究了MazEF在慢性感染中的作用，并破坏了mazF的表达。缺乏mazF生产的菌株显示生物膜生长增加，生物膜抗生素耐受性降低。在mazF::Tn背景下，icaADBC的缺失抑制了mazF破坏菌株的生长表型，表明表型依赖于ica。我们在小鼠动物模型中证实了这些表型。与野生型菌株相比，失去mazF导致细菌负担增加，小鼠存活率降低，这表明失去mazF基因导致金黄色葡萄球菌毒力增加。虽然缺乏mazF基因表达增加了金黄色葡萄球菌的毒力，但在体内对抗生素更敏感。综合起来，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到慢性感染的转变中发挥了关键作用，而慢性感染仅用抗生素很难根除。手术感染是医院最常见的感染类型之一。金黄色葡萄球菌是与这种感染相关的最常见病原体。这些感染是有弹性的，很难根除，因为细菌形成生物膜，一种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的抵抗力更强。细菌如何产生这种耐药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，抑制生物膜的形成，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慢性感染，不能用抗生素根除，但毒性较低。这种基因不仅使细菌对抗生素更有耐受性，而且使细菌对宿主更有耐受性。
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.