Dynamically chiral phosphonic acid-type metallo-β-lactamase inhibitors

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Antimicrobial Resistance

Background:

• Antibiotic resistance, particularly metallo-β-lactamase (MBL) mediated resistance, poses a significant global health threat.
• MBLs inactivate broad-spectrum β-lactam antibiotics, limiting treatment options.
• Currently, no clinically approved inhibitors exist for MBLs.

Purpose of the Study:

• To develop novel inhibitors targeting metallo-β-lactamases (MBLs) that can adapt to structural variations.
• To investigate the potential of dynamically chiral phosphonic acids as MBL inhibitors.

Main Methods:

• Synthesis of dynamically chiral phosphonic acids.
• Assessment of bacterial membrane penetration.
• In vitro inhibition assays against NDM-1, VIM-2, and GIM-1 MBLs.
• Cytotoxicity assays on human cells.

Main Results:

• Dynamically chiral phosphonic acids were synthesized and demonstrated effective inhibition of NDM-1, VIM-2, and GIM-1.
• These compounds exhibit good bacterial membrane penetration and are non-toxic to human cells.
• Both stereoisomers of the phosphonic acids bind to the MBL active site, targeting Zn ions and mimicking the transition state.

Conclusions:

• Dynamically chiral phosphonic acids represent a novel class of MBL inhibitors with broad applicability.
• Their adaptability to enzyme structural diversity and dual stereoisomer binding may overcome resistance development.
• These findings offer a promising avenue for combating infections caused by MBL-producing bacteria.