Kinga Virág Gulyás completes PhD in the search for metallo-β-lactamase inhibitors

Kinga Virág Gulyás, PhD student at Uppsala Antibiotic Center, defended her thesis "Exploring phosphonic acids for metallo-β-lactamase inhibition. In search of new strategies to fight antibiotic resistance." on 8 May 2026 at Uppsala University. Kinga is the fifth member of UAC's second cohort to defend.

A gap at the heart of antibiotic resistance treatment

β-Lactam antibiotics are the most prescribed antibiotics worldwide, and metallo-β-lactamases (MBLs) are among the most serious threats to their continued use. These bacterial enzymes degrade β-lactams, including last-resort carbapenems, making them ineffective. Combination therapy pairing an antibiotic with an enzyme inhibitor is an established strategy against resistance, but no MBL inhibitors currently exist on the market. Kinga's thesis directly addresses this gap.

Phosphonic acids as a new inhibitor platform

Kinga developed and evaluated multiple series of phosphonic acid-based compounds as candidate MBL inhibitors. The work spanned synthesis, biological testing, and structural characterisation using NMR spectroscopy, X-ray crystallography, and molecular docking. Across all series, a consistent finding emerged: the phosphonic acid group binds to the zinc ions in the enzyme's active site, an interaction seemingly conserved across the clinically most relevant MBL family. The compounds showed inhibitory activity against purified enzymes, were non-cytotoxic to human cells, and were able to cross the Gram-negative outer membrane.

Her thesis was arranged in four main projects and corresponding papers:

• Paper I developed dynamically chiral phosphonic acids, with the ability to change conformations, which had broad-spectrum activity against three different MBLs (VIM-2, NDM-1, and GIM-1). Their stereodynamic flexibility allowed both conformations to bind the MBL VIM-2, albeit with opposite orientations, a design feature with potential for adapting to enzyme variants.
• Paper II explored structural modifications to the core scaffold, showing that VIM-2 tolerates alterations that diminish activity against NDM-1 and GIM-1, providing useful information for understanding selectivity.
• Papers III and IV investigated α-aminophosphonic acids. Replacing an amide linker with an amine improved potency against VIM-2 and GIM-1, and halogenation enhanced this effect further. A separate series introduced natural amino acid scaffolds, yielding the first inhibitors in this compound class with activity against IMP-1, currently one of the most difficult MBL targets to address.

A versatile scaffold for future development

Taken together, Kinga's work establishes phosphonic acids as a viable and adaptable platform for MBL inhibitor development. The compounds' drug-like properties, membrane permeability, and confirmed binding mode make them credible lead candidates for further development toward clinical application.

UAC congratulates Kinga on a thesis that makes a genuine contribution to one of the most pressing challenges in antibiotic resistance research today.