PI3K/PKB signaling network as a host target to enhance bacterial ingestion and clearance.

Antibiotic resistance, driven by the misuse of antibiotics and the slow pace of new drug development, has led to a global rise in multidrug-resistant bacteria (MDRB), posing a major public health challenge. Host-directed therapies that enhance innate immune responses offer promising alternatives to traditional antibiotics. This review focuses on the central role of the PI3K/PKB (Akt) signaling pathway in phagocytosis and bacterial inactivation across both primitive phagocytes, such as Dictyostelium discoideum, and mammalian immune cells. In Dictyostelium, PI3K/PKB signaling coordinates the maturation of phagosomes and the fusion of phagolysosomes, processes essential for bacterial killing. Similarly, in immune cells, this pathway regulates cytoskeletal remodeling, vesicle trafficking, and the degradation of microbes. Specific pathogens, including Mycobacterium tuberculosis and Salmonella, subvert PI3K/PKB to evade immune responses, highlighting the pathway's dual role in host defense and pathogen survival. Targeting PI3K/PKB signaling or its inhibitory regulators may enhance phagocytic efficiency and restore immune function. Thus, PI3K/PKB represents a critical module in innate immunity and a compelling target for next-generation antimicrobial strategies.