Metallo-β-Lactamase Inhibitor Phosphonamidate Monoesters

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 beta-lactam antibiotics. Inhibition of metallo-beta-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-beta-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-beta-lactamase-resistant bacteria.