Redirecionamento de fármacos e sinergia de medicamentos não-antibióticos e antibióticos no tratamento de doenças infecciosas

Abstract

The indiscriminate use of antimicrobials in monotherapy has led to the emergence of multiresistant bacterial strains, which are also one of the greatest threats to human health. Whiles antibiotic resistance presents alarming data on its occurrence, treatment options and new antibiotics are not being developed in time, requiring more and more the development of compounds that have satisfactory antibacterial properties. In this sense, the redirection of drugs appeared as an alternative to the traditional search for active substances, since it is a faster and more advantageous process. Thus, the present study aimed, in the first article, to present to the scientific community the current research on the repositioning of non-antibiotic drugs against bacteria. In the second manuscript, the synergistic antibacterial activity of sertraline and disulfiram was analyzed as candidates for redirection. In the first article, we report that among the main advantages of repositioning are the availability of pharmacological data and toxicology, as well the as less expense in its development, together with success rates that reach 30%, recent approval by the Food and Drug Administration and also the possibility of synergies between itself or in combination with antimicrobials. The pharmacological classes currently involved in repositioning are nonsteroidal antiinflammatory drugs, antidepressants, antipsychotics, antialcoholism, neuroprotectors, antirheumatics, antidiarrheals, tuberculostatics and cardiovascular. We refer to 19 nonantibiotic drugs which have antibacterial activity against several strains, both Gram-positive and Gram-negative. In the second manuscript, we report the antibacterial activity of disulfiram and sertraline medications. The former was active against Gram-positive standard strains, while the second showed activity against both Gram-positive and Gram-negative and potent activity against five Staphylococcus spp.. clinical isolates. The combination of these two drugs was synergistic with the two strains of Staphylococcus aureus, and when associated with antimicrobials sulfamethoxazole/trimethoprim and ciprofloxacin, 8 synergism events occurred. Sertraline demonstrated potentiated bactericidal activity with disulfiram. Dissulfiram and sertraline, two non-antibiotic drugs, are promising alternatives for repositioning in the treatment of bacterial infections. However, additional studies, using different techniques, are necessary to elucidate the mechanisms of action involveds.