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

Abstract

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.