Antimicrobial Peptides Beyond the Petri Dish: Translational Barriers to Therapeutic Development

Abstract Antimicrobial peptides (AMPs) are promising antibiotics with rapid bactericidal mechanisms, broad-spectrum activity, and efficacy against drug-resistant pathogens. Yet, despite decades of research and development of many active AMPs, translation to the clinic remains limited. Although AMPs kill bacteria efficiently under optimized conditions, the same properties that enable membrane disruption - cationic charge, amphipathicity, and hydrophobicity - also cause their sequestration, degradation, and inactivation in biological fluids and tissues. This review examines how the major administration routes shape AMP pharmacokinetics and identifies the barriers that must be overcome for effective clinical translation. Each route imposes different limitations: oral delivery is limited by proteolytic degradation, bile sequestration, and poor absorption; intravenous administration by plasma protein binding, proteolysis, restricted tissue penetration, and nephrotoxicity; inhaled delivery by sequestration and inactivation in mucus and pulmonary surfactant; and topical delivery by impaired diffusion, sequestration, and proteolysis within wound and biofilm matrices. These limitations should be addressed from the outset of AMP design, with clear strategies on how to control serum binding, protect against protease digestion, and optimize charge and hydrophobic moment, to off–target interactions and toxicity. A pharmacologically informed approach that incorporates these barriers as design constraints is essential to transform AMPs into clinically effective drugs.