Emerging non-antibiotic strategies for combating intracellular pathogens

Intracellular pathogens, which can evade antibiotic killing and host immune defenses by taking refuge within host cells, play a crucial and often underappreciated role in the disease burden of persistent bacterial infections. Pathogens residing in phagocytic cells will disseminate from the initial infectious focus to other tissues via the bloodstream, leading to unpredictable infection relapse and metastasis. While antibiotics remain the primary treatment for infections, the emergence of antibiotic-tolerant persisters and antibiotic-resistant strains necessitates the exploration of alternative approaches for combating intracellular pathogens. In this review, we first provide a brief overview of the survival mechanisms of pathogens within professional or non-professional phagocytic cells, and correlation with antibiotic resistance. Furthermore, we summarize our current understanding of emerging non-antibiotic strategies to scavenge these difficult-to-treat intracellular pathogens, including the utilization of antibacterial materials, the adoption of engineered living materials, and the activation of host immune responses. Finally, we briefly discuss the application prospect of above-mentioned strategies, the challenges associated with advancing them to clinical trials, and the promising future directions for developing next-generation antibacterial approaches against intracellular pathogens.