Inhibition of metallo-B-lactamases by bisthiazolidines

JAVIER MARCELO GONZALEZ; MARIANO GONZALEZ; ALEJANDRO J. VILA

Albuquerque

Congreso; American Crystallographic Association Annual Meeting 2014; 2014

American Crystallographic Association

The efficacy of antibiotics has been recentlychallenged by the worldwide dissemination of genes encoding acquired metallo-β-lactamases (MBLs). These zinc-dependent hydrolases are able to confermultiresistance to β-lactam antibiotics in many pathogenic andopportunistic bacteria, leading to an urgent need for MBL inhibitors or newgenerations of β-lactam antibiotics insensitive to MBL-mediated inactivation.    We designed,synthesized and tested (both in vitroand in model systems in vivo) a novelgroup of bisthiazolidine MBL-inhibitors. Such compounds exhibit inhibitionconstants in the micromolar range against MBLs from different pathogens,including K. pneumoniae NDM-1 and IMP-1,B. cereus BcII, and E. meningoseptica GOB-18. As part as ourcurrent efforts to improve these compounds inhibiting power, we performedadditional structural studies through 1H-NMR and X-raycrystallography in order to characterize protein-ligand interactions at themolecular level. We solved X-ray crystal structures for MBLs in complex withseveral bisthiazolidine inhibitors, which shed light on their binding andinhibition modes. Our results will be contrasted against current proposedreaction mechanisms, together with available in vitro MBL inhibitors.This work has been supported by grants from NIAID-NIH(R01AI100560-01) and DOE-LDRD (20120776PRD4).