RESUMO
Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.
Assuntos
Antibacterianos/uso terapêutico , Depsipeptídeos/uso terapêutico , Lipopeptídeos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Permeabilidade da Membrana Celular/efeitos dos fármacos , Daptomicina/química , Daptomicina/uso terapêutico , Depsipeptídeos/síntese química , Depsipeptídeos/farmacocinética , Depsipeptídeos/toxicidade , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Lepidópteros/efeitos dos fármacos , Lepidópteros/microbiologia , Lipopeptídeos/síntese química , Lipopeptídeos/farmacocinética , Lipopeptídeos/toxicidade , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Metilação , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Testes de Sensibilidade MicrobianaRESUMO
Ultra-selective and ultra-sensitive probes for hypochlorous acid (HOCl), one of the most poorly understood reactive oxygen species (ROS), are urgently needed to unravel the HOCl functions in important biological processes such as development and innate immunity. Based on a selective oxidative O-dearylation reaction of 2,6-dichlorophenol toward HOCl over other reactive oxygen species, we have developed a novel fluorescent probe HKOCl-3 for HOCl detection with ultra-selectivity, ultra-sensitivity and a rapid turn-on response. The functional robustness of HKOCl-3 for endogenous HOCl detection and imaging has been thoroughly scrutinized in multiple types of phagocytes and in vivo imaging of live intact zebrafish embryos. Furthermore, HKOCl-3 has been successfully applied to the detection of endogenous HOCl by a 96-well microplate assay and flow cytometry. Therefore, HKOCl-3 holds great promise as a versatile molecular tool that enables innovative investigation of HOCl biology and ROS-related diseases in multiple detection modalities.
