Host-directed antimicrobial peptide biomaterials for combating Gram-negative bacterial infections

Antimicrobial resistance (AMR) represents a defining crisis in modern infectious disease medicine. Gram-negative microbes such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae are becoming more resistant than ever. Traditional methods of treatment using antibiotics are ineffective because of the presence of several envelope layers, active efflux pumps, and biofilm production. In contrast, bacteriolytic therapy can exacerbate host immunopathology owing to systemic endotoxin release. Host-defense peptides are thus being explored for their ability to kill bacteria, neutralize lipopolysaccharide (LPS), and modulate innate immune responses in a single treatment; however, clinical use remains hindered by their low stability, high binding to serum proteins, and narrow therapeutic index. In this review, we will discuss the use of biomaterial platforms in the design of peptide-based therapeutics to not only increase their efficacy by reducing peptide clearance but also optimize the immunological environment in which these peptides operate. We will discuss the role of various characteristics, such as surface chemistry, mechanical stiffness, and protein corona, in influencing macrophage polarization and downstream signaling pathways. In addition, we point out a significant limitation within this area of research: many preclinical studies continue to use minimum inhibitory concentration and hemolysis values, which fail to account for the host-directed effects that make these approaches significant. For future progress in this realm, new endpoints are required, along with more clinically relevant animal models and a true incorporation of peptide design into biomaterials engineering.