In Silico Design of Antimicrobial Peptides against Carbapenem-Resistant Acinetobacter baumannii Infections with Enhanced Activity by Nanoformulation

Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a critical public health menace. Its resistance to last-resort antibiotics highlights the urgent need for innovative treatment approaches. Antimicrobial peptides (AMPs) are promising candidates to address this challenge. AMPs have distinct mechanisms and a low likelihood of inducing resistance. In this study, we designed a water-soluble cationic AMP, “T2–02.” This was achieved using AMP database screening and in silico modeling with genetic algorithms (GAs). T2–02 has a net +7 charge at physiological pH and is composed of 21 amino acid residues. This charge facilitates strong electrostatic interactions with negatively charged microbial membranes. Moreover, the helical secondary structure of T2–02 enhances amphipathicity, enabling effective membrane insertion. When tested against Gram-negative CRAB isolates, T2–02 showed strong antibacterial activity. It also demonstrated outstanding biocompatibility, with low cytotoxicity and a minimal inhibitory concentration (MIC) of 8–16 μg/mL. Its therapeutic potential was further enhanced by the use of a liposomal nanodelivery method. This significantly improved T2–02’s loading efficiency. The liposomal strategy amplified its antimicrobial efficacy, reducing MICs by 2- to 4-fold. It also further minimized cytotoxicity. These results position T2–02 as a promising candidate for combating CRAB infections.