隐匿性甲氧西林耐药金黄色葡萄菌（OS-MRSA）感染常因转变为显性广谱耐药而难以控制，甲氧西林耐药基因A（mecA）易突变是其发生的重要原因，但机制不明且不易甄别。我们在前期发现高毒力OS-MRSA的基础上，进一步预实验发现mecA碱基插入突变的回复引起该菌株显性耐药，且在回复过程中转录因子SigB和转录偶联因子Mfd表达增加，而生长指数明显降低。生物信息学分析提示SigB可调控Mfd表达，而Mfd可能促进mecA回复突变。据此我们提出假说：SigB/Mfd途径促进mecA回复突变致OS-MRSA转变为显性耐药。本课题拟：①探索耐药性转变过程中菌株生长及SigB/Mfd表达规律，建立OS-MRSA筛选方法；②阐明SigB上调Mfd表达的分子机制；③揭示Mfd促进mecA回复突变的作用机制。本研究有望建立OS-MRSA诊断方法，阐明其耐药性转变机制，为OS-MRSA感染诊治提供新的理论依据。

Oxacillin-susceptible methicillin-resistant Staphylococcus aureus (OS-MRSA) infections are difficult to treat when oxacillin resistance emerges after exposure of subinhibitory antibiotic. The secondary mutation of the methicillin resistance gene A (mecA) is an important factor for the establishment of oxacillin resistance. However, the mechanism of this transition is unknown and difficult to determine. Recently, we identified a highly virulent clinical isolate of OS-MRSA, and we also found that the reversion mutation involved a base-pair-deletion mutation in the mecA gene, which caused the strain to revert to oxacillin resistance. Moreover, the expression of transcription factor SigB and transcription coupling factor Mfd was increased during this process, whereas the bacterial growth index was clearly decreased. A bioinformatic analysis suggested that SigB regulated mfd gene expression, and Mfd could promote the mecA reversion mutation. Therefore, we hypothesize that the SigB/Mfd pathway promotes the reversion mutation of the mecA gene, leading to the conversion of OS-MRSA to MRSA. In the present study, we aim to explore: ① the characteristic of OS-MRSA growth and the expression profile of SigB and Mfd during its conversion to MRSA, and establish an OS-MRSA screening method; ② the molecular mechanism of Mfd upregulation by SigB; ③ the mechanism by which Mfd promotes the reversion mutation of the mecA gene among OS-MRSA strains. Our study will provide the mechanistic insight into the drug resistance transition from OS-MRSA to MRSA, thus providing a theoretical basis for the diagnosis and treatment of OS-MRSA infections and allowing the establishment of diagnostic methods.