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2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases

DOI: 10.1039/D0SC05172A DOI Help

Authors: Maria-Agustina Rossi (Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR)) , Veronica Martinez (Universidad de la República (UdelaR)) , Philip Hinchliffe (University of Bristol) , Maria F. Mojica (Case Western Reserve University; Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Universidad El Bosque) , Valerie Castillo (Universidad de la República (UdelaR)) , Diego M. Moreno (Instituto de Química de Rosario (IQUIR, CONICET-UNR); University of Florida) , Ryan Smith (University of Bristol) , Brad Spellberg (Los Angeles County and University of Southern California (LAC + USC) Medical Center) , George L. Drusano (University of Florida) , Claudia Banchio (Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR); Universidad Nacional de Rosario) , Robert A. Bonomo (Louis Stokes Cleveland Department of Veterans Affairs Medical Center; Case Western Reserve University School of Medicine; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES)) , James Spencer (University of Bristol) , Alejandro J. Vila (Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR); Universidad Nacional de Rosario) , Graciela Mahler (Universidad de la República (UdelaR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science , VOL 17

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 17212

Open Access Open Access

Abstract: Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., Ki = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(II) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than D/L-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.

Diamond Keywords: Enzymes

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
d0sc05172a.pdf

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)