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
BACKGROUND: Advances in tissue clearing and molecular labeling methods are enabling unprecedented optical access to large intact biological systems. These developments fuel the need for high-speed microscopy approaches to image large samples quantitatively and at high resolution. While light sheet microscopy (LSM), with its high planar imaging speed and low photo-bleaching, can be effective, scaling up to larger imaging volumes has been hindered by the use of orthogonal light sheet illumination. RESULTS: To address this fundamental limitation, we have developed light sheet theta microscopy (LSTM), which uniformly illuminates samples from the same side as the detection objective, thereby eliminating limits on lateral dimensions without sacrificing the imaging resolution, depth, and speed. We present a detailed characterization of LSTM, and demonstrate its complementary advantages over LSM for rapid high-resolution quantitative imaging of large intact samples with high uniform quality. CONCLUSIONS: The reported LSTM approach is a significant step for the rapid high-resolution quantitative mapping of the structure and function of very large biological systems, such as a clarified thick coronal slab of human brain and uniformly expanded tissues, and also for rapid volumetric calcium imaging of highly motile animals, such as Hydra, undergoing non-isomorphic body shape changes.