RESUMO
Inhibition of S. aureus diapophytoene desaturase (CrtN) could serve as an alternative approach for addressing the tricky antibiotic resistance by blocking the biosynthesis of carotenoid pigment which shields the bacterium from host oxidant killing. In this study, we designed and synthesized 44 derivatives with piperonyl scaffold targeting CrtN and the structure-activity relationships (SARs) were examined extensively to bring out the discovery of 21b with potent efficacy and better hERG safety profile compared to the first class CrtN inhibitor benzocycloalkane derivative 2. Except the excellent pigment inhibitory activity against wild-type S. aureus, 21b also showed excellent pigment inhibition against four pigmented MRSA strains. In addition, H2O2 killing and human whole blood killing assays proved 21b could sensitize S. aureus to be killed under oxidative stress conditions. Notably, the murine study in vivo validated the efficacy of 21b against pigmented S. aureus Newman, vancomycin-intermediate S. aureus Mu50 and linezolid-resistant S. aureus NRS271.
Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Farmacorresistência Bacteriana/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Butóxido de Piperonila/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Linezolida/farmacologia , Meticilina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxirredutases/metabolismo , Butóxido de Piperonila/análogos & derivados , Butóxido de Piperonila/química , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade , Vancomicina/farmacologiaRESUMO
Previous work demonstrated that a commercial formulation of piperonyl butoxide (PBO) did inhibit the activity of some plant proteolytic enzymes. In this paper, the effect of pure PBO and nine pure PBO homologues (PBOH) appropriately synthesized toward bromelain and papain was studied in hydrocarbon solution using the bis(2-ethylhexyl)sodium sulfosuccinate (AOT) reverse micellar system. This study establishes that the majority of these compounds show, in vitro, interesting protease inhibition activities. The benzodioxole and dihydrobenzofuran structures, in particular, 5-[2-(2-butoxyethoxy)ethoxymethyl]-benzo[1,3]dioxole (EN 1-40) and 6-[2-(2-butoxyethoxy)ethoxymethyl]-5-propyl-2,3-dihydrobenzofuran (EN 16-5), respectively, appear to be responsible for protease inhibition. Measures of octanol/water partition coefficients on PBO and PBOH have demonstrated that water solubility plays a fundamental role in the expression of protease inhibition activity.