Caerin 1.1/1.9 peptides control Acinetobacter baumannii infection through combined antibacterial and host-directed immunomodulatory mechanisms

Introduction Acinetobacter baumannii is a major multidrug-resistant (MDR) pathogen associated with high morbidity and mortality, driven not only by antibiotic resistance but also by its ability to persist intracellularly and disrupt host immune homeostasis. Host-directed antimicrobial strategies that combine bactericidal activity with immune modulation are therefore urgently needed. Caerin peptides 1.1 (F1) and 1.9 (F3), derived from Australian tree frogs, have demonstrated broad antimicrobial activity, but their combined antibacterial and immunomodulatory mechanisms remain incompletely understood. Methods We evaluated the antimicrobial and host-directed effects of F1/F3 using in vitro A549 epithelial infection models and an in vivo murine skin-injury infection model. Antibacterial activity was assessed by minimum inhibitory concentration (MIC) assays and colony-forming unit (CFU) quantification. Host cell responses were analyzed using viability, LDH release, reactive oxygen species (ROS), and apoptosis assays. Immune modulation in vivo was investigated by flow cytometry, multiplex immunofluorescence, and cytokine profiling. Results F1/F3 exhibited potent antibacterial activity against A. baumannii (MIC 3.75 μg/mL) with minimal cytotoxicity to host cells. The peptides significantly reduced intracellular bacterial burden while alleviating infection-induced oxidative stress and early apoptosis. In vivo, F1/F3 treatment reduced bacterial colonization, improved tissue integrity, and reshaped the immune microenvironment. This included increased macrophage infiltration with a shift toward a reparative phenotype, reduced neutrophil accumulation, enhanced dendritic cell presence, and coordinated upregulation of pro- and anti-inflammatory cytokines, including IL-6, IL-12, IFN-γ, IL-10, and TGF-β, without altering TNF-α levels. Discussion These findings demonstrate that F1/F3 exert a dual mode of action by combining direct antibacterial effects with host-directed immunomodulation. By integrating microbial suppression, immune reprogramming, and tissue repair, caerin peptides represent promising candidates for the development of next-generation therapies against MDR A. baumannii infections.