Efeito de derivados de 1,10-fenantrolina sobre cepas de Acinetobacter baumannii produtoras de carbapenemases

• Autor(a) principal: Mendes, Roberta Ferreira Ventura
• Data de Publicação: 2019
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Repositório Institucional da Universidade Federal do Espírito Santo (riUfes)
• Texto Completo: http://repositorio.ufes.br/handle/10/14421
• topic: Doenças Infecciosas e Parasitárias; Acinetobacter baumannii; Resistência a fármacos; 1,10-fenantrolina; Drug-resistance; 1,10-phenanthroline; Fendione; Cu-fendione; Ag-fendione; Drug-synergism; Galleria mellonella; Mouse; subject.br-rjbn

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.