金黄色葡萄球菌的耐药性不仅与耐药基因表达有关，还与持留菌形成、入侵及细胞内存活有关，是治疗失败的重要因素之一。多因素参与细菌持留菌的形成，其中PhoU是重要的调控因子。经生物信息学分析，我们发现金葡菌和表葡菌基因组中存在2个phoU同源基因（phoU1和phoU2），而大肠埃希菌含1个phoU。初步研究显示phoU1敲除可减少金葡菌持留菌的形成，而对表葡菌无影响，提示PhoU同源物在不同细菌中作用机制不同。因此，本课题将构建金葡菌USA500 phoU1或phoU2单基因敲除株和phoU1-phoU2双基因敲株，研究其对金葡菌持留菌形成、毒力、侵袭力及胞内存活的影响；比较表达谱，分析金葡菌PhoU同源物可能调控的代谢通路，并通过其代谢产物或底物进行验证；研究PhoRP /YycGF对PhoU同源物表达的调控，阐明PhoU同源物调控金黄色葡萄球菌相关代谢途径与持留菌形成及细菌毒力的机制。

Antibiotics resistant of Staphylococcus aureus is not only related to expression of drug resistant genes, but also related to persister formation, invading and surviving in the host cells. Persister formation is one of factors resulting in the failure of treatment of infections. Multiple factors involve in persister formation, and PhoU homologue is an important regulator. The bacteria shared distinct mechanisms of PhoU, but its function is currently unknown. With bioinformatics analysis, we have identified two phoU homologues（phoU-1 and phoU-2）in the genomes of S. aureus and S. epidermidis, which is different from that of E. coli (only one phoU exits). In our preliminary study, phoU1 knockout reduced persister formation of S. aureus, but no effect on the Staphylococcus epidermidis. For investigating S. aureus’s phoU homologues functions and mechanisms in the persister formation, virulence, invasiveness and intracellular survival, we shall use a S. aureus virulent strain (USA500) to construct phoU homologous genes knock-out strains, as ∆phoU1, ∆phoU2 or ∆phoU1-phoU2. By comparison the transcriptomes of the gene knock-out strains with that of the parent strains, we shall identified the metabolism pathways which may regulated by PhoU homologues, and further validate by detection of metabolic products or subtracts in the pathway. Then the interaction of PhoU homologue with two component system, PhoRP /or YycG will be investigated. This study shall elucidate mechanism of PhoU homologue in regulation of S. aureus metabolism pathways involving persister formation and bacterial virulence.