Vaborbactam

Vaborbactam

Clinical data
Trade names	Carbavance
Routes of administration	IV
ATC code	J01CG (WHO)
Pharmacokinetic data
Excretion	Renal
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
PubChem CID	56649692
ChemSpider	35035409 Y
UNII	1C75676F8V
CompTox Dashboard (EPA)	DTXSID901027690
ECHA InfoCard	100.235.136
Chemical and physical data
Formula	C12H16BNO5S
Molar mass	297.13 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1

Vaborbactam is a broad-spectrum beta-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 beta-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.

According to a Medicines Company press release, as of June 2016 a combination of vaborbactam with the carbapenem antibiotic meropenem had met all pre-specified primary endpoints in a phase III clinical trial in patients with complicated urinary tract infections. The company planned to submit an NDA to the FDA in early 2017.

Biochemistry

Carbapenemases are a family of beta-lactamase enzymes distinguished by their broad spectrum of activity and their ability to degrade carbapenem antibiotics, which are frequently used in the treatment of multidrug-resistant gram-negative infections. Although there are multiple classification schemes in existence, they can be broadly divided into two different categories based on the mechanism they use to hydrolyze the lactam ring in their substrates and further subdivided based on sequence homology using the Ambler classification system. Metallo-beta-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. Serine carbapenemase-catalyzed hydrolysis employs a simple three-step mechanism featuring acylation and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral transition state.

Boronic acids are unique 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. Based on data from Hecker et al., vaborbactam is a potent inhibitor of a variety of beta-lactamases, exhibiting a 69-nanomolar $K_{i}$ against the KPC-2 carbapenemase and even lower inhibition constants against CTX-M-15 and SHV-12.

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 beta-lactamase inhibitors, and in fact boronic acids like bortezomib have previously been investigated or developed as inhibitors of various human proteases. Vaborbactam, however, is highly specific, with an IC50 >> 1 mM against all human serine hydrolases for which it has been tested. Consistent with its high in 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. Hecker et al. argue this specificity results from the higher affinity of human serine hydrolases for linear substrates similar to their endogenous substrates; in their view, these substrate preferences suggest it is unsurprising that human serine hydrolases have low affinity for a cyclic boronate like vaborbactam.