Kinga Virág Gulyás: Exploring phosphonic acids for metallo-β-lactamase inhibition: In search of new strategies to fight antibiotic resistance

Abstract

The Global Antibiotic Research & Development Partnership (GARDP) estimates that antibiotic resistance claims one life in every 6 seconds. It is currently associated with 5 million deaths annually, a number that continues to rise. A major challenge in combating antibiotic resistance is the emergence of metallo-β-lactamase enzymes that degrade our most used antibiotics, the β-lactams. Combination therapy, which involves administering an enzyme inhibitor alongside an existing β-lactam antibiotic, presents a viable strategy to address this issue. However, no metallo-β-lactamase inhibitors are currently available on the market, underscoring the urgent need for their development.

This work describes the development of new phosphonic acid-based metallo-β-lactamase inhibitors and studies their binding to the target metallo-β-lactamase enzymes. Phosphorous-containing molecules are promising inhibitor candidates, which act as transition state analogues that bind to the zinc ions essential for the metallo-β-lactamase activity. The synthesis and bioactivities of three sets of phosphonic acid-type inhibitors are described. These compounds proved to be active on purified metallo-β-lactamases (micromolar to nanomolar IC50) as well as on living bacteria, they were Gram-negative membrane permeable and not cytotoxic to human cells. Their binding event was evaluated by solution NMR spectroscopy, X-ray crystallography, molecular docking and molecular dynamics studies. The key interaction between the phosphonic acid core and the enzymes’ zinc ions was determined. These findings are expected to contribute to the development of clinically applicable metallo-β-lactamase inhibitors.