Vaborbactam

Vaborbactam

Clinical data
Routes of administration	IV
ATC code	None
Identifiers
IUPAC name {(3R,6S)-2-Hydroxy-3-[2-(thiophen-2-yl)acetamido]- 1,2-oxaborinan-6-yl}acetic acid
CAS Number	1360457-46-0
PubChemCID	56649692
DrugBank	DB12107
ChemSpider	35035409
UNII	1C75676F8V
KEGG	D10998
CompTox Dashboard(EPA)	DTXSID901027690
ECHA InfoCard	100.235.136
Chemical and physical data
Formula	C12H16BNO5S
Molar mass	297.13g·mol−1
3D model (JSmol)	Interactive image
SMILES B1([C@H](CC[C@H](O1)CC(=O)O)NC(=O)CC2=CC=CS2)O
InChI InChI=1S/C12H16BNO5S/c15-11(7-9-2-1-5-20-9)14-10-4-3-8(6-12(16)17)19-13(10)18/h1-2,5,8,10,18H,3-4,6-7H2,(H,14,15)(H,16,17)/t8-,10-/m0/s1 Key:IOOWNWLVCOUUEX-WPRPVWTQSA-N

Vaborbactam(INN)is a non-β-lactamβ-lactamase inhibitordiscovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as anantibioticby 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-negativebacterialinfections.

In the United States, thecombination drugmeropenem/vaborbactam(Vabomere) is approved by theFood and Drug Administrationfor complicatedurinary tract infectionsandpyelonephritis.

Biochemistry

Vaborbactam is aboronic acidβ-lactamase inhibitor with a high affinity forserineβ-lactamases, includingKlebsiella pneumoniaecarbapenemase (KPC). Vaborbactam inhibits a variety of β-lactamases, exhibiting a 69 nMK_iagainst 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 siteserine in a serine carbapenemase. This property enables them to function astransition state analogsof 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 tohydrolyzethelactamring in theirsubstrates:Metallo-β-lactamases contain boundzincions in their active sites and are therefore inhibited by chelating agents likeEDTA,whileserinecarbapenemases feature anactive siteserinethat participates in the hydrolysis of the substrate.Serine carbapenemase-catalyzed hydrolysis employs a three-stepmechanismfeaturingacylationand deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedraltransition state.

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 likebortezomibhave previously been investigated or developed as inhibitors of various human proteases.Vaborbactam, however, is a highly specific β-lactamase inhibitor, with anIC₅₀>> 1 mM against all human serine hydrolases against which it has been tested.Consistent with its highin vitrospecificity, vaborbactam exhibited a good safety profile in human phase I clinical trials, with similar adverse events observed in both placebo and treatment groups.Hecker et al. argue this specificity results from the higher affinity of humanproteasesto linear molecules; thus it is expected that aboronheterocyclewill have zero effect on them.