RESUMO
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.
Assuntos
Antibacterianos , Cefalosporinas , Inibidores de beta-Lactamases , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cefalosporinas/química , Cefalosporinas/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/químicaRESUMO
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.
Assuntos
Marcadores de Afinidade/farmacologia , Compostos Azabicíclicos/farmacologia , Enterobacter cloacae/isolamento & purificação , Corantes Fluorescentes/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/química , Marcadores de Afinidade/síntese química , Marcadores de Afinidade/química , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/química , Enterobacter cloacae/enzimologia , Fluoresceínas/síntese química , Fluoresceínas/química , Fluoresceínas/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/químicaRESUMO
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.