RESUMO
Abietic and dehydroabietic acid are interesting diterpenes with a highly diverse repertoire of associated bioactivities. They have, among others, shown antibacterial and antifungal activity, potentially valuable in the struggle against the increasing antimicrobial resistance and imminent antibiotic shortage. In this paper, we describe the synthesis of a set of 9 abietic and dehydroabietic acid derivatives containing amino acid side chains and their in vitro antimicrobial profiling against a panel of human pathogenic microbial strains. Furthermore, their in vitro cytotoxicity against mammalian cells was evaluated. The experimental results showed that the most promising compound was 10 [methyl N-(abiet-8,11,13-trien-18-yl)-d-serinate], with an MIC90 of 60µg/mL against Staphylococcus aureus ATCC 25923, and 8µg/mL against methicillin-resistant S. aureus, Staphylococcus epidermidis and Streptococcus mitis. The IC50 value for compound 10 against Balb/c 3T3 cells was 45µg/mL.
Assuntos
Abietanos/química , Abietanos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Animais , Antifúngicos/química , Antifúngicos/farmacologia , Células 3T3 BALB , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Fungos/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
The combination of the dehydroabietic acid scaffold with different amino acids resulted in the discovery of a new class of hybrid compounds that targets both planktonic and biofilms bacteria in Staphylococcus aureus strains and are far more potent anti-biofilm agents than conventional antibiotics. Unlike dehydroabietic acid, these compounds can disrupt biofilms within a short time period and compromise the integrity of the bacterial membrane. Two of the compounds identified in our study are the most potent abietane-type anti-biofilm agents reported so far and display robust activity against pre-formed biofilms at concentrations only 3-6-fold higher than those required to inhibit biofilm formation. Their easy preparation based on proteolysis-resistant d- and unusual amino acids makes them useful chemical probes to gain a deeper understanding of bacterial biofilms and outstanding candidates for further development into new drugs to fight infections.
