Abstract
The emergence of multidrug-resistant bacteria (MDR), particularly in cytosolic methicillin-resistant Staphylococcus aureus (MRSA) are causing substantial infections and posing an urgent global threat to public health. The era of antibiotic resistant has hindered the development of antibiotics that solely target bacteria, highlighting the need for alternative therapeutic strategies. Host-acting therapies are emerging as a dominant approach to address the shortage of novel antibiotics and prevent novel-resistant bacteria. Herein, we explored the modes of action of five flavonoids that combat cytosolic MRSA through host-acting antibacterial effects. Both in vitro and in vivo models demonstrated the efficacy of flavonoids in combating cytosolic MRSA lung infections. Transcriptomic and proteomic analyses revealed that the antibacterial targets of these flavonoids are linked to the phagosome pathway. Mechanistic studies further showed that flavonoids enhance lysosomal acidification, identifying it as a viable target for host-acting antibacterial drugs. These findings suggest that flavonoid treatments represent a promising host-acting therapeutic strategy for combating cytosolic MRSA infections.