Síntese, caracterização, avaliação da atividade antimicrobiana e biodistribuição de Jeleína-I contra isolados clínicos de Acinetobacter baumannii

Abstract

Emerging bacterial infections pose a serious threat to human health. In this scenario, Acinetobacter baumannii is of particular concern due to its resistance to antimicrobials, especially carbapenems. In addition, the stagnation in the development of efficient antimicrobials underlines the need to search for new therapeutic strategies. Antimicrobial peptides such as jelleine-I appear to be a promising class. In this work, we characterized the activity of jelleine-I alone or in combination with conventional antimicrobials against clinical isolates of A. baumannii with different resistance phenotypes and furthermore investigated the peptide-membrane interaction in biomimetic media and its potential as a radiotracer peptide. Jelleine-I showed promising in vitro results demonstrating its potential as an effective antimicrobial agent against carbapenem-resistant strains of A. baumannii. An integrated analysis of ITC, SPR and DLS data as well as evidence of bacteriolysis indicates that the mechanism of action involves an interactive interaction with the bacterial membrane that promotes its rupture. Significant synergy with antimicrobial classes such as carbapenems, fluoroquinolones and aminoglycosides were also observed, as well as resensitization of strains to colistin, highlighting its potential as a therapeutic adjuvant capable of restoring the efficacy of antimicrobials compromised by antimicrobial resistance. Notably, jelleine-I, alone or in combination with meropenem, outperformed polymyxin B in inhibiting biofilms, an aspect of great clinical relevance considering that it is associated with persistent infections and treatment failure. However, exposure of the AC 37 strain to the peptide led to an increase in the minimum bactericidal concentration (MBC), suggesting a possible induction of resistance, challenging the common assumption that antimicrobial peptides have a low propensity to select for resistance. In parallel, the 99m-Tc-HYNIC-βAla-Jelleine-I complex showed preferential retention at sites of bacterial infection, making it a promising diagnostic agent by images to infeccious focus due to A.baumannii. With its broad-spectrum antimicrobial activity, anti-biofilm activity, synergy with causative antimicrobials and potential for diagnostic use, Jelleine-I represents a conceptual advance in the fight against A. baumannii infections, although it also highlights the challenges in translating AMPs from research to clinical practice.