Efeito de derivados de 1,10-fenantrolina sobre cepas de Acinetobacter baumannii produtoras de carbapenemases
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Data
2019-10-31
Autores
Mendes, Roberta Ferreira Ventura
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Universidade Federal do Espírito Santo
Resumo
Therapeutic options are becoming limited for patients infected with Acinetobacter baumannii due to increased resistance to commonly used antimicrobial agents, such as carbapenems. The development of new antimicrobials became a priority. In this sense, the present study aimed to evaluate the effects of 1,10-phenanthroline and its derivatives, fendione, Cu-fendione and Ag-fendione, alone and combined with carbapenems in different strains of A. Baumannii producing carbapenemases. For this purpose were investigated: (i) the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (CBM) of the compounds, meropenem (MPM) and imipenem (IMP); (ii) the effect of combining the compounds with MPM and IMP by checkerboard and time-kill curve; (iii) the effect of combinations in a Galleria mellonella model and (iv) the effect of Ag-fendione in a mouse model. The results obtained by determining MIC and CBM demonstrated excellent antimicrobial activity by the four compounds against all strains (n=26). The mean MIC values of 1.10 phenanthroline, fendione, Cu-fendione and Ag-fendione were 12.98, 1.98, 1.56 and 1.56 μg / ml, respectively. Through the checkerboard, synergistic and additive action was verified in the combinations of compounds with IMP and additivity when combined with MPM. The time-kill curve method showed that combinations containing ½ x MIC of Ag-fendione or Cu-fendione produced an additive effect for 6 hours. It was observed that the combination of MPM with Ag-fendione was able to eradicate bacterial cells. Ag-fendione and Cu-fendione showed bactericidal effect in 6 hours, but it was not dose-dependent. The combination of the compound Ag-fendione with MPM showed statistically significant superiority in relation to the agents alone in a model of G. mellonella. The compound Ag-fendione was able to reduce the infection caused by A. baumannii in a model of infection in mice at a concentration of 75 µg / kg. Treatment with ½ × CMI of 1.10-phenanthroline and its derivatives inhibited approximately 68% of the biomass and 60% of the cell viability of A. baumannii in biofilm. Thus, the results obtained demonstrate the potential of 1,10 phenanthroline, fendione, Cu-fendione and Ag-fendione as drug candidates alone or combined with carbapenemic antimicrobials for A. baumannii.
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Acinetobacter baumannii , Resistência a fármacos , 1,10-fenantrolina , Drug-resistance , 1,10-phenanthroline , Fendione , Cu-fendione , Ag-fendione , Drug-synergism , Galleria mellonella , Mouse