Host–Pathogen Interactions and Peptide-Based Therapeutics in Intracellular Bacterial Infections

Intracellular bacterial infections remain a global health challenge due to their insidious and persistent nature. This review focuses on host-pathogen interactions, referring to the dynamic struggle between host immune defenses and bacterial invasion/survival mechanisms. A thorough understanding of host cell bactericidal mechanisms, as well as the invasion and evasion strategies employed by intracellular bacteria, is essential for developing novel antibacterial agents. Crucially, traditional antibiotics often fail due to poor membrane permeability, rapid efflux, or suboptimal subcellular accumulation, leading to treatment failure and resistance. To break this deadlock, peptide-based therapeutics offer a transformative frontier through: (1) precision delivery via cell-penetrating peptides (CPPs); (2) multimodal bactericidal mechanisms to minimize resistance; and (3) host-directed therapies that reactivate innate defense pathways. Furthermore, we highlight optimization strategies ranging from rational chemical design to AI-driven generative discovery. To facilitate clinical translation, we conclude by outlining future directions: integrating ultralarge library screening (e.g., phage/mRNA display) to expand discovery; employing chemical modifications and nanoencapsulation to overcome metabolic fragility; and developing stimuli-responsive "smart" platforms for spatiotemporally precise, low-toxicity delivery. Finally, implementing compartment-specific PK/PD models to quantify subcellular drug exposure is essential.