RESUMO
One of the most important threats to public health is the appearance of multidrug-resistant pathogenic bacteria, since they are the cause of a high number of deaths worldwide. Consequently, the preparation of new effective antibacterial agents that do not generate antimicrobial resistance is urgently required. We report on the synthesis of new linear cationic antibacterial polytriazoles that could be a potential source of new antibacterial compounds. These polymers were prepared by thermal- or copper-catalyzed click reactions of azide and alkyne functions. The antibacterial activity of these materials can be modulated by varying the size or nature of their side chains, as this alters the hydrophilic/hydrophobic balance. Antibacterial activity was tested against pathogens of the ESKAPE group. The P3TD polymer, which has butylated side chains, was found to have the highest bactericidal activity. The toxicity of selected polytriazoles was investigated using human red blood cells and a human gingival fibroblast cell line. The propensity of prepared polytriazoles to induce resistance in certain bacteria was studied. Some of them were found to not produce resistance in methicillin-resistant Staphylococcus aureus or Pseudomonas aeruginosa. The interaction of these polytriazoles with the Escherichia coli membrane produces both depolarization and disruption of the membrane.
RESUMO
Novel linear cationic poly(amide aminotriazole)s (PATnD) with secondary amine groups in the backbone were obtained by using azide-alkyne 1,3-dipolar cycloaddition reactions: metal- and solvent-free (thermal conditions, PATTnD) or copper(I)-catalyzed (Sharpless conditions, PATCnD). PATnD were investigated in vitro against strains of E. coli, P. aeruginosa, S. aureus, and S. epidermidis. Hemolytic activity was tested using human red blood cells (hRBC), and very low or no hemolytic activity was observed. The cytotoxicity of PATnD polymers against Human Gingival Fibroblasts (HGnF) cells was concentration-dependent, and significant differences between PATT1D and PATC1D were observed. The ability of these polymers to induce resistance against both Gram-positive and Gram-negative bacteria was also assessed. Studied bacterial strains acquired resistance to catalytic polymers (PATCnD) in initial passages meanwhile resistance to thermal polymers (PATTnD) appears in later passages, being the increase of the minimum inhibitory concentration lower than in catalytic polymers. This result, together with the higher biocidal capacity of thermal polymers compared to catalytic ones, seems to suggest an influence of the regiospecificity of the polymers on their antibacterial characteristics. This study also demonstrates that PAT1D polymers, which do not appear to have strong hydrophobic residues, can exert significant antimicrobial activity against Gram-positive bacteria such as S. epidermidis. This pair of polymers, PATC1D and PATT1D, displays the greatest antimicrobial activity while not causing significant hemolysis along with the lowest susceptibility for resistance development of the polymers evaluated.
