Metallo-β-lactamase inhibitor phosphonamidate monoesters

Katarzyna Palica, Manuela Vorácová, Susann Skagseth, Anna Andersson Rasmussen, Lisa Allander, Madlen Hubert, Linus Sandgren, Hanna-Kirst Leiros, Hanna Andersson, Máté Erdélyi

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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 21st 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.
    Original languageEnglish
    Pages (from-to)4550–4562
    JournalACS Omega
    Volume7
    Issue number5
    DOIs
    Publication statusPublished - 2022 Jan 25

    Subject classification (UKÄ)

    • Organic Chemistry

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