CHARACTERIZATION OF THE ANTIMICROBIAL ACTIVITY OF CU-FENDION AND AG-FENDION METAL COMPLEXES IN CARBAPENEMIC-RESISTANT CLINICAL STRAINS OF Acinetobacter baumannii
Name: INGRID VIANEZ PEREGRINO
Publication date: 07/11/2024
Examining board:
Name |
Role |
|---|---|
| ANDRÉ LUÍS SOUZA DOS SANTOS | Coorientador |
| ANNA CLARA MILESI GALDINO | Examinador Externo |
| MARTA HELENA BRANQUINHA DE SÁ | Examinador Externo |
| MOISES PALACI | Examinador Interno |
Summary: 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 g/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.
