2. Academic Validation
  3. Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes

Rational Design of Benzobisheterocycle Metallo-β-Lactamase Inhibitors: A Tricyclic Scaffold Enhances Potency against Target Enzymes

  • J Med Chem. 2024 Mar 14;67(5):3795-3812. doi: 10.1021/acs.jmedchem.3c02209.
Valentina Villamil 1,  Maria-Agustina Rossi 2,  Maria F Mojica 3 4,  Philip Hinchliffe 5,  Verónica Martínez 1,  Valerie Castillo 1,  Cecilia Saiz 1,  Claudia Banchio 2 6,  Mario A Macías 7,  James Spencer 5,  Robert A Bonomo 3 4 8 9 10,  Alejandro Vila 2 4 6,  Diego M Moreno 6 11,  Graciela Mahler 1
Affiliations

Affiliations

  • 1 Laboratorio de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República (UdelaR), Avda. General Flores, 2124 Montevideo, Uruguay.
  • 2 Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Ocampo y Esmeralda, S2002LRK Rosario, Argentina.
  • 3 Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 44106 Cleveland, Ohio, United States.
  • 4 CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), 44106 Cleveland, Ohio, United States.
  • 5 School of Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, University Walk, BS8 1TD Bristol, U.K.
  • 6 Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, S2002LRK Rosario, Argentina.
  • 7 Crystallography and Chemistry of Materials, CrisQuimMat, Department of Chemistry, Universidad de los Andes, 111711 Bogotá, Colombia.
  • 8 Departments of Medicine, Pharmacology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, 44106 Cleveland, Ohio, United States.
  • 9 Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 44106 Cleveland, Ohio, United States.
  • 10 Clinical Scientist Investigator, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 44106 Cleveland, Ohio, United States.
  • 11 Instituto de Química Rosario (IQUIR, CONICET-UNR), Ocampo y Esmeralda, S2002LRK Rosario, Argentina.
PMID: 38373290 DOI: 10.1021/acs.jmedchem.3c02209
Abstract

Antimicrobial resistance is a global public health threat. Metallo-β-lactamases (MBLs) inactivate β-lactam Antibiotics, including carbapenems, are disseminating among Gram-negative bacteria, and lack clinically useful inhibitors. The evolving bisthiazolidine (BTZ) scaffold inhibits all three MBL subclasses (B1-B3). We report design, synthesis, and evaluation of BTZ analogues. Structure-activity relationships identified the BTZ thiol as essential, while carboxylate is replaceable, with its removal enhancing potency by facilitating hydrophobic interactions within the MBL active site. While the introduction of a flexible aromatic ring is neutral or detrimental for inhibition, a rigid (fused) ring generated nM benzobisheterocycle (BBH) inhibitors that potentiated carbapenems against MBL-producing strains. Crystallography of BBH:MBL complexes identified hydrophobic interactions as the basis of potency toward B1 MBLs. These data underscore BTZs as versatile, potent broad-spectrum MBL inhibitors (with activity extending to Enzymes refractory to Other inhibitors) and provide a rational approach to further improve the tricyclic BBH scaffold.

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