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| ECHA InfoCard | 100.235.136 |
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| Formula | C12H16BNO5S |
| Molar mass | 297.13 g·mol−1 |
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Vaborbactam (INN)[1] is a non-β-lactamβ-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as anantibiotic 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 ofgram-negative bacterialinfections.[2]
In the United States, thecombination drugmeropenem/vaborbactam (Vabomere) is approved by theFood and Drug Administration for complicatedurinary tract infections andpyelonephritis.[3] The combination was approved for medical use in Canada in December 2024.[4]
Vaborbactam is aboronic acid β-lactamase inhibitor with a high affinity forserine β-lactamases, includingKlebsiella pneumoniae carbapenemase (KPC).[5]Vaborbactam inhibits a variety of β-lactamases, exhibiting a 69 nMKi 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 theactive site serine in a serine carbapenemase. This property enables them to function astransition state analogs of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes.[2]
Carbapenemases can be broadly divided into two different categories based on the mechanism they use tohydrolyze thelactam ring in theirsubstrates: Metallo-β-lactamases contain boundzinc ions in their active sites and are therefore inhibited by chelating agents likeEDTA, whileserine carbapenemases feature anactive siteserine that participates in the hydrolysis of the substrate.[6] Serine carbapenemase-catalyzed hydrolysis employs a three-stepmechanism featuringacylation and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedraltransition state.[6][7]
Given their mechanism of action, the possibility of off-target effects brought about through inhibition of endogenous serine hydrolases is an obvious possible concern in the development of boronic acid β-lactamase inhibitors, and in fact boronic acids likebortezomib have previously been investigated or developed as inhibitors of various human proteases.[2] Vaborbactam, however, is a highly specific β-lactamase inhibitor, with anIC50 >> 1 mM against all human serine hydrolases against which it has been tested.[2] Consistent with its highin vitro specificity, vaborbactam exhibited a good safety profile in human phase I clinical trials, with similar adverse events observed in both placebo and treatment groups.[8] Hecker et al. argue this specificity results from the higher affinity of humanproteases to linear molecules; thus it is expected that aboronheterocycle will have zero effect on them.
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