Caracterización biológica de una nueva serie de compuestos químicos con actividad antimicrobiana (Tesis de Grado, TFG)
Antimicrobial resistance has become a serious global health problem, not only because resistant bacteria cause millions of deaths worldwide, but also because fewer antibiotics are approved to treat these infections. Currently, there is a great need to find new antimicrobial agents effective against multi-drug resistant strains.
In this project, we have characterized the antimicrobial activity of a library containing 47 chemical compounds with related structural features never tested before in biological processes. To this aim, a screening strategy was followed to select those compounds showing in vitro activity and without cytotoxicity.
First, a single concentration assay (single shot) was performed against 17 bacterial strains, including Gram-positives, Gram-negatives, and mycobacteria. Thirteen compounds were selected with activity at 50 μM against at least one of the strains. Second, dose-response and time-kill kinetics assays were also performed, selecting 5 compounds with bactericidal activity against Gram-positive bacteria at concentrations ranging from 0.78 to 50 μM. Third, cytotoxicity assays in human hepatic cells were performed to determine selectivity indexes (S.I); these ranged from 3.4 to 70.5. Fourth, concentrations of 5 μM were found not mutagenic by the Ames’ Test. Finally, structure-activity relationship (SAR) studies defined chemical structural features determining the compounds’ antimicrobial activity.
In summary, we have identified active compounds against Gram-positive bacteria with good S.I., which opens a new research line with the potential to develop new antimicrobial agents. Future assays may include more detailed studies of in vitro and in vivo activity, toxicity, determination of the molecular mechanism of action and medicinal chemistry efforts in order to optimize these series of compounds.