Caracterização da atividade antimicrobiana dos complexos metálicos Cu-fendiona e Ag-fendiona em cepas clínicas de Acinetobacter baumannii resistentes a carbapenêmicos e com diferentes perfis de virulência
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Data
2024-11-07
Autores
Peregrino, Ingrid Vianez
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Universidade Federal do Espírito Santo
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Continuous efforts are essential for developing new anti-infective agents in response to the increasing threat of antimicrobial resistance. Exploring the pharmacodynamic (PD) properties and activity profiles of antimicrobial candidates enables rational optimization of these compounds' development, maximizing their therapeutic potential. Our research group has been investigating the therapeutic potential of metal-based complexes derived from 1,10-phenanthroline-5,6-dione (phendione) against critical pathogens. Previous studies have demonstrated the efficacy of Ag-phendione and Cu phendione against carbapenem-resistant (CRAb) and multidrug-resistant Acinetobacter baumannii strains, both in planktonic cells and biofilms. In this study, we characterized the antimicrobial activity of Cu-phendione and Ag-phendione and determined their PD parameters against six clinical CRAb strains and the ATCC 19606. We also investigated the antivirulence potential of these compounds by identifying virulence attributes and pathogenic mechanisms in 26 clinical CRAb strains. Exposure response assays revealed strong bactericidal effects at low concentrations, with predominantly time-dependent activity and peak efficacy between 6 and 12 hours. Fractionated dosing strategies showed sustained antimicrobial efficacy, with two 0.5×MIC doses administered 6 hours apart resulting in complete eradication of all strains within 24 hours. Substantial inoculum variations did not significantly alter MIC values, confirming consistent bactericidal activity across different bacterial densities. At 3.12 µg/mL, both compounds were able to eradicate over 97% of the tested inocula. Additionally, both exhibited short post-antibiotic effects (PAE), with Ag-phendione displaying slower growth recovery than Cu-phendione, with average PAE durations of 1.857 h and 0.714 h, respectively. The modified disk-diffusion (“TDtest”) showed no evidence of tolerance or heteroresistance. The investigation of virulence-associated features revealed notable heterogeneity among the studied strains, with variations in levels of mucoviscosity, motility, biofilm formation, and autoaggregation capacity. The analysis of cell surface properties indicated a negative correlation between mucoidy and hydrophobicity levels, while all isolates exhibited an electronegative surface charge. However, no direct correlation was observed between these surface characteristics and biofilm formation capacity. In the Galleria mellonella infection model, larval mortality rates suggested diversity in pathogenic strategies among strains, though no direct correlation was found between specific virulence attributes and overall pathogenicity. While previous studies have demonstrated the antibiofilm activity of these compounds, in the present study, the high heterogeneity of the sample group prevented the evaluation of the complexes' impact on specific virulence attributes. Thus, our conclusions focus on the broad therapeutic potential of Cu phendione and Ag-phendione as promising alternatives for treating CRAb infections, highlighting their antimicrobial properties and favorable PD profiles across diverse resistance and virulence patterns in A. baumannii
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Complexos metálicos , Compostos derivados da fendiona , Propriedades farmacodinâmicas , A. baumannii resistente a carbapenêmicos , Virulência bacteriana , A. baumannii biofilme , Metal complexes , Phendione-compounds , Pharmacodynamics , Carbapenem-resistant A. baumannii , Bacterial virulence , A. baumannii biofilm