Emerging host-directed strategies for overcoming drug resistance and immune evasion in Staphylococcus aureus infections

Staphylococcus aureus poses a significant global threat to both human and animal health. Bacterial-targeted therapies are limited by strong selective pressures (e.g., mecA-mediated β-lactam resistance) and the pathogen's remarkable capacity for phagocyte intracellular survival-a strategy that allows them to evade antibiotics and the immune system, ultimately leading to persistent infections. These factors highlight the urgent need for alternative strategies to combat bacterial infections. This review explores host-directed therapies (HDTs) as alternative strategies for combating S. aureus infections, aiming to overcome limitations of current treatments and contribute to the development of novel or combination therapies. HDTs offer several advantages, including a reduced risk of bacterial resistance, a broad antimicrobial spectrum, and the potential for synergy with antibiotics to shorten treatment duration and even treat persistent intracellular infections. Target-based precision drug design shows strong promise in addressing off-target effect challenges. This review provides an overview of key host factors involved in S. aureus pathogenesis, emphasizing therapeutic agents targeting these factors, their mechanisms of action, and pharmacological profiles. These recent advancements are crucial in the ongoing efforts to combat S. aureus infections.