A Novel AI-Designed Antimicrobial Peptide Synergistically Potentiates Aminoglycosides against Colistin- and Carbapenem-ResistantAcinetobacter baumannii

Abstract The urgent necessity for new antibiotics becomes glaringly evident with the relentless rise of multidrug-resistant (MDR) Acinetobacter baumannii in clinical environments, where its infections lead to alarmingly high mortality rates. Antimicrobial peptides (AMPs) represent a promising novel option to combat nosocomial infections caused by MDR A. baumannii . In this study, six novel synthetic peptides were designed through generative artificial intelligence (AI) and synthesized for further experiments. Peptides AIG-R1, AIG-R4, and AIG-R5 showed potent broad-spectrum antibacterial activity against Gram positive and Gram negative pathogens. One of the peptides, AIG-R5, was effective even against colistin and carbapenem-resistant strains of A. baumannii, prevented biofilm formation, and eradicated established biofilms by 60%. Notably, AIG-R5 enhanced the activity of different antibiotics and was found to exhibit synergistic activity with antibiotics from the Aminoglycoside class. The combination of AIG-R5 and Tobramycin at 1/8×MIC and 1/4×MIC effectively reduced pre-formed biofilms of carbapenem resistant A. baumannii more than either component alone, as documented by confocal laser scanning microscopy (CLSM). Significant dose reduction and negligible cytotoxicity exhibited by AIG-R5 with aminoglycosides further encourages evaluation of the combination’s therapeutic potential in vivo against MDR A. baumannii infections.