RESUMEN
Host Defense Peptides (HDPs) have gained considerable interest due to the omnipresent threat of bacterial infection as a serious public health concern. However, development of HDPs is impeded by several drawbacks, such as poor selectivity, susceptibility to proteolytic degradation, low-to-moderate activity and requiring complex syntheses. Herein we report a class of lipo-linear α/urea-γ-AApeptides with a hybrid backbone and low molecular weight. The heterogeneous backbone not only enhances chemodiversity, but also shows effective antimicrobial activity against Gram-positive bacteria and is capable of disrupting bacterial membranes and killing bacteria rapidly. Given their low molecular weight and ease of access via facile synthesis, they could be practical antibiotic agents.
Asunto(s)
Amidas/farmacología , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Bacterias Grampositivas/efectos de los fármacos , Lipopéptidos/química , Péptidos/química , Urea/química , Amidas/química , Secuencia de Aminoácidos , Antibacterianos/química , Péptidos Catiónicos Antimicrobianos/química , Permeabilidad de la Membrana Celular , Evaluación Preclínica de Medicamentos , Bacterias Gramnegativas/efectos de los fármacos , Humanos , Lipopéptidos/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Peso Molecular , Péptidos/farmacología , Peptidomiméticos/química , Peptidomiméticos/farmacología , Técnicas de Síntesis en Fase Sólida , Relación Estructura-ActividadRESUMEN
A carboxyl-ebselen-based layer-by-layer (LbL) film was fabricated by alternatively assembling carboxyl-ebselen immobilized polyethylenimine (e-PEI) and alginate (Alg) onto substrates followed by salt annealing and cross-linking. The annealed films exhibiting significantly improved stability are capable of generating nitric oxide (NO) from endogeneous S-nitrosothiols (RSNOs) in the presence of a reducing agent. The NO generation behaviors of different organoselenium species in solution phase are compared and the annealing mechanism to create stable LbL films is studied in detail. An LbL film coated polyurethane catheter is capable of generating physiological levels of NO from RSNOs even after blood soaking for 24 h, indicating potential antithrombotic applications of the coating. Further, the LbL film is also demonstrated to be capable of reducing living bacterial surface attachment and killing a broad spectrum of bacteria, likely through generation of superoxide (O(2)(·-)) from oxygen. This type of film is expected to have potential application as an antithrombotic and antimicrobial coating for different biomedical device surfaces.