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Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase

DOI: 10.1021/acsinfecdis.5b00046 DOI Help

Authors: Mariano M. González (Universidad Nacional de Rosario (UNR)) , Magda Kosmopoulou (University of Bristol) , Maria F. Mojica (Case Western Reserve University) , Valerie Castillo (Universidad de la República) , Philip Hinchliffe (University of Bristol) , Ilaria Pettinati (University of Oxford) , Jurgen Brem (University of Oxford) , Christopher J. Schofield (University of Oxford) , Graciela Mahler (Universidad de la República) , Robert A. Bonomo (Case Western Reserve University) , Leticia I. Llarrull (Universidad Nacional de Rosario (UNR)) , James Spencer (University of Bristol) , Alejandro J. Vila (Universidad Nacional de Rosario (UNR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases , VOL 1 (11)

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 8922 , 313

Abstract: Pathogenic Gram-negative bacteria resistant to almost all ?-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-?-lactamases (MBLs) produced by these bacteria inactivate most ?-lactam antibiotics, including the carbapenems, which are “last line therapies” for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of ?-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with ?-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 ?M). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.

Journal Keywords: Antibiotic Resistance; Inhibitors; Bisthiazolidines; Metallo-?-Lactamase; Ndm-1

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)