α-Aminophosphonate inhibitors of metallo-ßlactamases NDM-1 and VIM-2

The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-ss-lactamases is of particular concern as these enzymes degrade ss-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-ss-lactamases could allow the continued use of existing ss-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, whose applicability is becoming ever more limited. The design, synthesis, and NDM-1, VIM-2, and GIM-1 inhibitory activities (IC50 4.1-506 mu M) of a series of novel non-cytotoxic alpha-aminophosphonate-based inhibitor candidates are presented herein. We disclose the solution NMR spectroscopic and computational investigation of their NDM-1 and VIM-2 binding sites and binding modes. Whereas the binding modes of the inhibitors are similar, VIM-2 showed a somewhat higher conformational flexibility, and complexed a larger number of inhibitor candidates in more varying binding modes than NDM-1. Phosphonate-type inhibitors may be potential candidates for development into therapeutics to combat metallo-ss-lactamase resistant bacteria.

Automated summary

The upswing of antibiotic resistance, particularly resistance mediated by bacterial metallo-ss-lactamases, poses an escalating threat to human health. This study presents a series of novel non-cytotoxic alpha-aminophosphonate-based inhibitor candidates and investigates their inhibitory activities and binding modes. The findings suggest that phosphonate-type inhibitors may be potential therapeutic candidates for combating metallo-ss-lactamase resistant bacteria.