Staphylococcus aureus (S. aureus) is one of the critical clinical pathogens which can cause multiple diseases ranging from skin infections to fatal sepsis. S. aureus is generally considered to be an extracellular pathogen. However, more and more evidence has shown that S. aureus can survive inside various cells. Folate plays an essential role in multiple life activities, including the conversion of serine and glycine, the remethylation of homocysteine to methionine, and the de novo synthesis of purine /dTMP, et al. More and more studies reported that S. aureus intracellular infection requires the involvement of folate metabolism. This review focused on the mechanisms of folate metabolism and related substances affecting S. aureus infection. Loss of tetrahydrofolic acid (THF)-dependent dTMP directly inhibits the nucleotide synthesis pathway of the S. aureus due to pabA deficiency. Besides, trimethoprim-sulfamethoxazole (TMP/SMX), a potent antibiotic that treats S. aureus infections, interferes in the process of the folate mechanism and leads to the production of thymidine-dependent small-colony variants (TD-SCVs). In addition, S. aureus is resistant to lysostaphin in the presence of serine hydroxymethyltransferase (SHMT). We provide new insights for understanding the molecular pathogenesis of S. aureus infection.

金黄色葡萄球菌( S. aureus ) 是一种重要的临床病原体，可引起从皮肤感染到致命性败血症等多种疾病。金黄色葡萄球菌通常被认为是细胞外病原体。然而，越来越多的证据表明，金黄色葡萄球菌可以在各种细胞内存活。叶酸在多种生命活动中起着至关重要的作用，包括丝氨酸和甘氨酸的转化、同型半胱氨酸再甲基化为甲硫氨酸、嘌呤/dTMP 的从头合成等。越来越多的研究报道金黄色葡萄球菌细胞内感染需要叶酸代谢的参与。本综述重点关注影响金黄色葡萄球菌感染的叶酸代谢和相关物质的机制。由于pabA缺乏，四氢叶酸 (THF) 依赖性 dTMP 的缺失直接抑制了金黄色葡萄球菌的核苷酸合成途径。此外，甲氧苄氨嘧啶-磺胺甲恶唑 (TMP/SMX) 是一种治疗金黄色葡萄球菌感染的强效抗生素，它会干扰叶酸机制的过程，并导致胸苷依赖性小菌落变异体 (TD-SCV) 的产生。此外，金黄色葡萄球菌在丝氨酸羟甲基转移酶 (SHMT) 存在的情况下对溶葡萄球菌素具有抗性。我们为理解金黄色葡萄球菌感染的分子发病机制提供了新的见解。