Vaborbactam

Vaborbactam (INN) is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the β-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.

In the United States, the combination drug meropenem/vaborbactam (Vabomere) is approved by the Food and Drug Administration for complicated urinary tract infections and pyelonephritis. The combination was approved for medical use in Canada in December 2024.

Biochemistry

Vaborbactam is a boronic acid β-lactamase inhibitor with a high affinity for serine β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC).

Vaborbactam inhibits a variety of β-lactamases, exhibiting a 69 nM Ki against the KPC-2 carbapenemase and even lower inhibition constants against CTX-M-15 and SHV-12. Boronic acids are unusual in their ability to reversibly form covalent bonds with alcohols such as the active site serine in a serine carbapenemase. This property enables them to function as transition state analogs of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes.

Carbapenemases can be broadly divided into two different categories based on the mechanism they use to hydrolyze the lactam ring in their substrates: Metallo-β-lactamases contain bound zinc ions in their active sites and are therefore inhibited by chelating agents like EDTA, while serine carbapenemases feature an active site serine that participates in the hydrolysis of the substrate.