Miao Zhao, Dongli Rong, Ling Chen, Shuzhen Cai, Yongcheng Lu, Jingsha Dai, Youxiong Zhang, Xianhu Wei, Xia Yang, Qingping Wu
Staphylococcus aureus, as a critical zoonotic and foodborne pathogen, not only triggers public health threats such as food poisoning but also acts as a leading cause of diverse clinical infections, including skin infections, pneumonia, and endocarditis. Confronted with the growing crisis of multidrug resistance in S. aureus, both phage therapy and probiotic therapy have emerged as promising alternative biological strategies; however, the current literature predominantly examines them in isolation. This review therefore aims to delineate the contemporary therapeutic challenges of drug-resistant S. aureus and to systematically compare the mechanisms and clinical translation of phages and probiotics within an integrated analytical framework. We first outline the current therapy landscape, then present side by side the molecular inhibitory mechanisms and clinical progress of both approaches, followed by a comparative analysis of their antibacterial mechanisms, clinical efficacy, and industrial challenges. Through this consolidated perspective, the review not only clarifies the distinct strengths and limitations of each strategy but also seeks to provide researchers and clinicians with a comprehensive mechanistic and evidence-based reference for developing novel antibacterial technologies and designing innovative therapeutic regimens. Ultimately, it highlights potential synergies between phages and probiotics, offering a forward-looking roadmap to overcome S. aureus resistance and advance personalized combinatorial therapies.