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

Valentina VillamilMaria-Agustina RossiMaria F MojicaPhilip HinchliffeVerónica MartínezValerie CastilloCecilia SaizClaudia BanchioMario A MacíasJames SpencerRobert A BonomoAlejandro VilaDiego Martín MorenoGraciela Mahler
Published in: Journal of medicinal chemistry (2024)
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.
Keyphrases
  • public health
  • antimicrobial resistance
  • escherichia coli
  • photodynamic therapy
  • ionic liquid
  • big data
  • molecular docking
  • amino acid