Vaborbactam (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway. Before the advent of motorized transportation, they also provided accomm ...

) is a non- β-lactam

β-lactamase inhibitor Beta-lactamases are a family of enzymes involved in bacterial antimicrobial resistance, resistance to β-lactam antibiotic, beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degra ...

discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

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 Gram-negative bacteria are bacteria that, unlike gram-positive bacteria, do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. Their defining characteristic is that their cell envelope consists ...

bacterial

infection An infection is the invasion of tissue (biology), tissues by pathogens, their multiplication, and the reaction of host (biology), host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmis ...

s. In the United States, the

combination drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

meropenem/vaborbactam (Vabomere) is approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

for complicated

urinary tract infection A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyel ...

s and

pyelonephritis Pyelonephritis is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications ...

. The combination was approved for medical use in Canada in December 2024.

Biochemistry

Vaborbactam is a

boronic acid A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, memb ...

β-lactamase inhibitor with a high affinity for

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

β-lactamases, including ''

Klebsiella pneumoniae ''Klebsiella pneumoniae'' is a Gram-negative, non-motile, encapsulated, lactose- fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar. Although found in the normal flora of the mo ...

'' carbapenemase (KPC). Vaborbactam inhibits a variety of β-lactamases, exhibiting a 69 nM K_i 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 In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

serine in a serine carbapenemase. This property enables them to function as

transition state analog Transition state analogs (transition state analogues), are chemical compounds with a chemical structure that resembles the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. Enzymes interact with a substrate by mea ...

s 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 Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

the

lactam A lactam is a Cyclic compound, cyclic amide, formally derived from an amino alkanoic acid through cyclization reactions. The term is a portmanteau of the words ''lactone'' + ''amide''. Nomenclature Greek_alphabet#Letters, Greek prefixes in alpha ...

ring in their substrates: Metallo-β-lactamases contain bound

zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...

ions in their active sites and are therefore inhibited by chelating agents like

EDTA Ethylenediaminetetraacetic acid (EDTA), also called EDTA acid, is an aminopolycarboxylic acid with the formula . This white, slightly water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-solubl ...

, while

carbapenemases feature an

that participates in the hydrolysis of the substrate. Serine carbapenemase-catalyzed hydrolysis employs a three-step

mechanism Mechanism may refer to: *Mechanism (economics), a set of rules for a game designed to achieve a certain outcome **Mechanism design, the study of such mechanisms *Mechanism (engineering), rigid bodies connected by joints in order to accomplish a ...

featuring

acylation In chemistry, acylation is a broad class of chemical reactions in which an acyl group () is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the foll ...

and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral

transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...

. 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 like

bortezomib Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is ...

have previously been investigated or developed as inhibitors of various human proteases. Vaborbactam, however, is a highly specific β-lactamase inhibitor, with an IC₅₀ >> 1 mM against all human serine hydrolases against 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

proteases A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products. They do ...

to linear molecules; thus it is expected that a

boron Boron is a chemical element; it has symbol B and atomic number 5. In its crystalline form it is a brittle, dark, lustrous metalloid; in its amorphous form it is a brown powder. As the lightest element of the boron group it has three ...

heterocycle A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

will have zero effect on them.

References

{{Authority control Carboxamides Antibiotics Beta-lactamase inhibitors Carboxylic acids Thiophenes Boronate esters