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

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dc.citation.titleChemical Science
dc.citation.volume12
dc.contributor.orcidhttps://orcid.org/0000-0003-4720-4070
dc.contributor.orcidhttps://orcid.org/0000-0002-3697-5219
dc.contributor.orcidhttps://orcid.org/0000-0001-8611-4743
dc.contributor.orcidhttps://orcid.org/0000-0002-1380-9824
dc.contributor.orcidhttps://orcid.org/0000-0001-5493-8537
dc.contributor.orcidhttps://orcid.org/0000-0002-4602-0571
dc.contributor.orcidhttps://orcid.org/0000-0002-7978-3233
dc.contributor.orcidhttps://orcid.org/0000-0003-0612-0516
dc.creatorRossi, María Agustina
dc.creatorMartínez, Verónica
dc.creatorHinchliffe, Philip
dc.creatorMojica, María F.
dc.creatorCastillo, Valerie
dc.creatorMoreno, Diego M.
dc.creatorSmith, Ryan
dc.creatorSpellberg, Brad
dc.creatorDrusano, George L.
dc.creatorBanchio, Claudia
dc.creatorBonomo, Robert A.
dc.creatorSpencer, James
dc.creatorVila, Alejandro J.
dc.creatorMahler, Graciela
dc.date.accessioned2024-04-15T19:50:01Z
dc.date.available2024-04-15T19:50:01Z
dc.date.issued2021-01-05
dc.description.abstractInfections 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.
dc.description.filFil: Rossi, María Agustina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Martínez, Verónica. Universidad de la República. Facultad de Química. Departamento de Química Orgánica. Laboratorio de Química Farmacéutica; Uruguay.
dc.description.filFil: Hinchliffe, Philip. University of Bristol. School of Cellular and Molecular Medicine; United Kingdom.
dc.description.filFil: Mojica, María F. Case Western Reserve University. School of Medicine. Infectious Diseases Department; United States.
dc.description.filFil: Mojica, María F. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Research Service; United States.
dc.description.filFil: Mojica, María F. Universidad El Bosque. Grupo de Resistencia Antimicrobiana y Epidemiología Hospitalaria; Colombia.
dc.description.filFil: Castillo, Valerie. Universidad de la República. Facultad de Química. Departamento de Química Orgánica. Laboratorio de Química Farmacéutica; Uruguay.
dc.description.filFil: Moreno, Diego M. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química de Rosario (IQUIR-CONICET); Argentina.
dc.description.filFil: Smith, Ryan. University of Bristol. School of Cellular and Molecular Medicine; United Kingdom.
dc.description.filFil: Spellberg, Brad. Los Angeles County and University of Southern California (LAC+USC) Medical Center; United States.
dc.description.filFil: Drusano, George L. University of Florida. Department of Pharmaceutics, College of Pharmacy. Center for Pharmacometrics and Systems Pharmacology; United States.
dc.description.filFil: Banchio, Claudia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. Research Service; United States.
dc.description.filFil: Bonomo, Robert A. Case Western Reserve University. School of Medicine. Departments of Medicine, Pharmacology, Molecular Biology and Microbiology, Biochemistry, Proteomics and Bioinformatics; United States.
dc.description.filFil: Bonomo, Robert A. Louis Stokes Cleveland Department of Veterans Affairs Medical Center. GRECC. Medical Service; United States.
dc.description.filFil: Bonomo, Robert A. CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology; United States.
dc.description.filFil: Spencer, James. University of Bristol. School of Cellular and Molecular Medicine; United Kingdom.
dc.description.filFil: Vila, Alejandro J. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Mahler, Graciela. Universidad de la República. Facultad de Química. Departamento de Química Orgánica. Laboratorio de Química Farmacéutica; Uruguay.
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH): R01AI063517, R01AI072219, R01AI100560, R01AI130060, R01AI117211
dc.description.sponsorshipCleveland Department of Veterans Affairs
dc.description.sponsorshipBiomedical Laboratory Research & Development Service of the VA Office of Research and Development: award number 1I01BX001974
dc.description.sponsorshipGeriatric Research Education and Clinical Center VISN 10
dc.description.sponsorshipUniversidad de la República. Comisión Académica de Posgrado (CAP-Udelar)
dc.description.sponsorshipUniversity of Bristol
dc.description.sponsorshipAgencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (Agencia I+D+i): PICT-2016-1657
dc.description.sponsorshipConsejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
dc.description.versionpeerreviewed
dc.format.extent1-11
dc.identifier.issn2041-6539
dc.identifier.urihttps://hdl.handle.net/2133/26890
dc.language.isoen
dc.publisherRoyal Society of Chemistry
dc.relation.publisherversionhttps://doi.org/10.1039/d0sc05172a
dc.relation.publisherversionhttps://pubs.rsc.org/en/content/articlelanding/2021/sc/d0sc05172a
dc.rightsopenAccess
dc.rights.holderRossi, María Agustina
dc.rights.holderMartínez, Verónica
dc.rights.holderHinchliffe, Philip
dc.rights.holderMojica, María F.
dc.rights.holderCastillo, Valerie
dc.rights.holderMoreno, Diego M.
dc.rights.holderSmith, Ryan
dc.rights.holderSpellberg, Brad
dc.rights.holderDrusano, George L.
dc.rights.holderBanchio, Claudia
dc.rights.holderBonomo, Robert A.
dc.rights.holderSpencer, James
dc.rights.holderVila, Alejandro J.
dc.rights.holderMahler, Graciela
dc.rights.holderUniversidad Nacional de Rosario
dc.rights.textAttribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectDrug resistance, multiple
dc.subjectDrug resistance, multiple, bacterial
dc.subjectBeta-lactam resistance
dc.subjectBeta-lactamase inhibitors
dc.subjectResistencia a múltiples medicamentos
dc.subjectFarmacorresistencia bacteriana múltiple
dc.subjectResistencia betalactámica
dc.subjectInhibidores de beta-lactamasas
dc.title2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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