RESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) cause more than 100,000 deaths each year, which need efficient and non-resistant antibacterial agents. SAR analysis of 162 flavonoids from the plant in this paper suggested that lipophilic group at C-3 was crucial, and then 63 novel flavonoid derivatives were designed and total synthesized. Among them, the most promising K15 displayed potent bactericidal activity against clinically isolated MRSA and VRE (MICs = 0.25-1.00 µg/mL) with low toxicity and high membrane selectivity. Moreover, mechanism insights revealed that K15 avoided resistance by disrupting biofilm and targeting the membrane, while vancomycin caused 256 times resistance against MRSA, and ampicillin caused 16 times resistance against VRE by the same 20 generations inducing. K15 eliminated residual bacteria in mice skin MRSA-infected model (>99 %) and abdominal VRE-infected model (>92 %), which was superior to vancomycin and ampicillin.
Assuntos
Antibacterianos , Flavonoides , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Enterococos Resistentes à Vancomicina , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/química , Flavonoides/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Animais , Camundongos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Infecções Estafilocócicas/tratamento farmacológico , HumanosRESUMO
It's urgent to discover new antibiotics along with the increasing emergence and dissemination of multidrug resistant (MDR) bacterial pathogens. In the present investigation, morusin exhibited rapid bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) by targeting the phospholipid of bacterial inner membrane, increasing membrane rigidity and disrupting bacterial homeostasis together with the membrane permeability, which caused fundamental metabolic disorders. Furthermore, morusin can also accumulate ROS, suppress H2S production, and aggravate oxidative damage in bacteria. Importantly, morusin also inhibited the spread of wounds and reduced the bacterial burden in the mouse model of skin infection caused by MRSA. It's a chance to meet the challenge of existing antibiotic resistance and avoid the development of bacterial resistance, given the multiple targets of morusin.
