Metallo-β-Lactamase Inhibitor Phosphonamidate Monoesters.

Palica K, Vorácová M, Skagseth S, Andersson Rasmussen A, Allander L, Hubert M, Sandegren L, Schrøder Leiros HK, Andersson H, Erdélyi M

ACS Omega 7 (5) 4550-4562 [2022-02-08; online 2022-01-25]

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.

Swedish NMR Centre (SNC)

PubMed 35155946

DOI 10.1021/acsomega.1c06527

Crossref 10.1021/acsomega.1c06527

pmc: PMC8830069

Publications 9.5.0