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Metallo-β-Lactamase Inhibitor Phosphonamidate Monoesters

[Image: see text] Being the second leading cause of death and the leading cause of disability-adjusted life years worldwide, infectious diseases remain—contrary to earlier predictions—a major consideration for the public health of the 21(st) century. Resistance development of microbes to antimicrobi...

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Detalles Bibliográficos
Autores principales: Palica, Katarzyna, Vorácová, Manuela, Skagseth, Susann, Andersson Rasmussen, Anna, Allander, Lisa, Hubert, Madlen, Sandegren, Linus, Schrøder Leiros, Hanna-Kirstirep, Andersson, Hanna, Erdélyi, Máté
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8830069/
https://www.ncbi.nlm.nih.gov/pubmed/35155946
http://dx.doi.org/10.1021/acsomega.1c06527
Descripción
Sumario:[Image: see text] Being the second leading cause of death and the leading cause of disability-adjusted life years worldwide, infectious diseases remain—contrary to earlier predictions—a major consideration for the public health of the 21(st) century. Resistance development of microbes to antimicrobial drugs constitutes a large part of this devastating problem. The most widely spread mechanism of bacterial resistance operates through the degradation of existing β-lactam antibiotics. Inhibition of metallo-β-lactamases is expected to allow the continued use of existing antibiotics, whose applicability is becoming ever more limited. Herein, we describe the synthesis, the metallo-β-lactamase inhibition activity, the cytotoxicity studies, and the NMR spectroscopic determination of the protein binding site of phosphonamidate monoesters. The expression of single- and double-labeled NDM-1 and its backbone NMR assignment are also disclosed, providing helpful information for future development of NDM-1 inhibitors. We show phosphonamidates to have the potential to become a new generation of antibiotic therapeutics to combat metallo-β-lactamase-resistant bacteria.