TY - JOUR
T1 - Metallo-β-lactamase inhibitor phosphonamidate monoesters
AU - Palica, Katarzyna
AU - Vorácová, Manuela
AU - Skagseth, Susann
AU - Andersson Rasmussen, Anna
AU - Allander, Lisa
AU - Hubert, Madlen
AU - Sandgren, Linus
AU - Leiros, Hanna-Kirst
AU - Andersson, Hanna
AU - Erdélyi, Máté
PY - 2022/1/25
Y1 - 2022/1/25
N2 - 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.
AB - 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.
U2 - 10.1021/acsomega.1c06527
DO - 10.1021/acsomega.1c06527
M3 - Article
C2 - 35155946
SN - 2470-1343
VL - 7
SP - 4550
EP - 4562
JO - ACS Omega
JF - ACS Omega
IS - 5
ER -