RESUMEN
Antibiotic resistance caused by ß-lactamases, particularly metallo-ß-lactamases, has been a major threat to public health globally. New Delhi metallo-ß-lactamase-1 (NDM-1) represents one of the most important metallo-ß-lactamases; the production of NDM-1 in bacterial pathogen significantly reduces the efficacy of ß-lactam antibiotics, including life-saving carbapenems. Herein, we have demonstrated stereochemically altered cephalosporins as potent inhibitors against NDM-1, as well as mutants of NDM. The structure and activity relationship (SAR) study on over twenty cephalosporin analogues discloses the stereochemistry and the substituents on 7-position and 3'-position of cephalosporin are critical to suppress the activity of NDM-1 and the optimal compound 1u exhibited an IC50 of 0.13 µM. Furthermore, a crystal complex of NDM-1 and 1u has been obtained, suggesting this cephalosporin derivative inhibits enzyme activity by the formation of a relatively stable hydrolytic product-NDM-1 intermediate. The discovery in this study may pave the way to turn cephalosporin, a natural substrate of ß-lactamase, into an effective NDM-1 inhibitor to combat antibiotic resistance.
Asunto(s)
Antibacterianos , Cefalosporinas , Inhibidores de beta-Lactamasas , Antibacterianos/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Cefalosporinas/química , Cefalosporinas/farmacología , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/químicaRESUMEN
Reported herein is a relebactam-derived fluorogenic reagent for covalent labeling of serine ß-lactamases (SBLs), which are the major causes of bacterial resistance to ß-lactam antibiotics. This highly selective imaging reagent generates over 300-fold stronger near-infrared fluorescence signals upon covalently bonding to SBLs, allowing wash-free visualization of live antimicrobial-resistant bacteria.
Asunto(s)
Marcadores de Afinidad/farmacología , Compuestos de Azabiciclo/farmacología , Enterobacter cloacae/aislamiento & purificación , Colorantes Fluorescentes/farmacología , Inhibidores de beta-Lactamasas/farmacología , beta-Lactamasas/química , Marcadores de Afinidad/síntesis química , Marcadores de Afinidad/química , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/química , Enterobacter cloacae/enzimología , Fluoresceínas/síntesis química , Fluoresceínas/química , Fluoresceínas/farmacología , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Inhibidores de beta-Lactamasas/síntesis química , Inhibidores de beta-Lactamasas/químicaRESUMEN
Reported herein is a fluorescence assay for the rapid screening of metallo-ß-lactamase (MBL) inhibitors. This assay employs a fluorogenic carbapenem CPC-1 as substrate and is compatible with all MBLs, including B1, B2 and B3 subclass MBLs. The efficiency of this assay was demonstrated by the rapid inhibition screening of a number of molecules against B2 MBL CphA and 2,3-dimercaprol was identified as a potent CphA inhibitor.
