Metallo-β-Lactamase Inhibitor Phosphonamidate Monoesters.
Katarzyna PalicaManuela VorácováSusann SkagsethAnna Andersson RasmussenLisa AllanderMadlen HubertLinus SandegrenHanna-Kirstirep Schrøder LeirosHanna AnderssonMáté ErdélyiPublished in: ACS omega (2022)
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.
Keyphrases
- gram negative
- klebsiella pneumoniae
- multidrug resistant
- infectious diseases
- public health
- escherichia coli
- magnetic resonance
- high resolution
- multiple sclerosis
- staphylococcus aureus
- solid state
- small molecule
- molecular docking
- healthcare
- binding protein
- protein protein
- solid phase extraction
- case control
- mass spectrometry
- molecularly imprinted
- risk assessment
- long non coding rna
- social media