Vaborbactam: Difference between revisions
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{{Short description|Chemical compound}} |
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{{Infobox drug |
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| DrugBank = DB12107 |
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| ChemSpiderID = 35035409 |
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| UNII = 1C75676F8V |
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'''Vaborbactam''' ([[International nonproprietary name|INN]])<ref name = "INN">{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75 | url = http://apps.who.int/medicinedocs/documents/s22359en/s22359en.pdf | publisher = World Health Organization | pages = 161–2}}</ref> is a non-[[Beta-lactam|β-lactam]] [[β-Lactamase inhibitor|β-lactamase inhibitor]] discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an [[Antibiotics|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 bacteria|gram-negative]] bacterial [[infection]]s.<ref name = "Hecker">{{cite journal | vauthors = Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, King P, Tsivkovski R, Sun D, Sabet M, Tarazi Z, Clifton MC, Atkins K, Raymond A, Potts KT, Abendroth J, Boyer SH, Loutit JS, Morgan EE, Durso S, Dudley MN | display-authors = 6 | title = Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 9 | pages = 3682–92 | date = May 2015 | pmid = 25782055 | doi = 10.1021/acs.jmedchem.5b00127 }}</ref> |
'''Vaborbactam''' ([[International nonproprietary name|INN]])<ref name = "INN">{{cite web | title = International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75 | url = http://apps.who.int/medicinedocs/documents/s22359en/s22359en.pdf | archive-url = https://web.archive.org/web/20170202000603/http://apps.who.int/medicinedocs/documents/s22359en/s22359en.pdf | url-status = dead | archive-date = February 2, 2017 | publisher = World Health Organization | pages = 161–2}}</ref> is a non-[[Beta-lactam|β-lactam]] [[β-Lactamase inhibitor|β-lactamase inhibitor]] discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an [[Antibiotics|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 bacteria|gram-negative]] bacterial [[infection]]s.<ref name = "Hecker">{{cite journal | vauthors = Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, King P, Tsivkovski R, Sun D, Sabet M, Tarazi Z, Clifton MC, Atkins K, Raymond A, Potts KT, Abendroth J, Boyer SH, Loutit JS, Morgan EE, Durso S, Dudley MN | display-authors = 6 | title = Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 9 | pages = 3682–92 | date = May 2015 | pmid = 25782055 | doi = 10.1021/acs.jmedchem.5b00127 | doi-access = free }}</ref> |
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In the United States, the [[combination drug]] [[meropenem/vaborbactam]] (Vabomere) is approved by the [[Food and Drug Administration]] for complicated [[urinary tract infection]]s and [[pyelonephritis]].<ref>{{Cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573955.htm | title = FDA approves new antibacterial drug | publisher = [[Food and Drug Administration]] | date = August 29, 2017}}</ref> |
In the United States, the [[combination drug]] [[meropenem/vaborbactam]] (Vabomere) is approved by the [[Food and Drug Administration]] for complicated [[urinary tract infection]]s and [[pyelonephritis]].<ref>{{Cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573955.htm | title = FDA approves new antibacterial drug | publisher = [[Food and Drug Administration]] | date = August 29, 2017}}</ref> |
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== Biochemistry == |
== Biochemistry == |
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Vaborbactam is a [[boronic acid]] β-lactamase inhibitor with a high affinity for [[serine]] β-lactamases, including ''[[Klebsiella pneumoniae]]'' carbapenemase (KPC).<ref name=exp>{{cite journal | vauthors = Burgos RM, Biagi MJ, Rodvold KA, Danziger LH | title = Pharmacokinetic evaluation of meropenem and vaborbactam for the treatment of urinary tract infection | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 14 | issue = 10 | pages = 1007–1021 | date = October 2018 | pmid = 30106599 | doi = 10.1080/17425255.2018.1511702 }}</ref> |
Vaborbactam is a [[boronic acid]] β-lactamase inhibitor with a high affinity for [[serine]] β-lactamases, including ''[[Klebsiella pneumoniae]]'' carbapenemase (KPC).<ref name=exp>{{cite journal | vauthors = Burgos RM, Biagi MJ, Rodvold KA, Danziger LH | title = Pharmacokinetic evaluation of meropenem and vaborbactam for the treatment of urinary tract infection | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 14 | issue = 10 | pages = 1007–1021 | date = October 2018 | pmid = 30106599 | doi = 10.1080/17425255.2018.1511702 | s2cid = 52006261 }}</ref> |
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Vaborbactam inhibits a variety of β-lactamases, exhibiting a 69 nM [[Dissociation constant|K<sub>i</sub>]] 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 analog]]s of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes.<ref name = "Hecker" /> |
Vaborbactam inhibits a variety of β-lactamases, exhibiting a 69 nM [[Dissociation constant|K<sub>i</sub>]] 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 analog]]s of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes.<ref name = "Hecker" /> |
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Carbapenemases can be broadly divided into two different categories based on the mechanism they use to [[Hydrolysis|hydrolyze]] the [[lactam]] ring in their [[Substrate (chemistry)|substrates]]: Metallo-β-lactamases contain bound [[zinc]] ions in their active sites and are therefore inhibited by chelating agents like [[Ethylenediaminetetraacetic acid|EDTA]], while [[serine]] carbapenemases feature an [[active site]] [[serine]] that participates in the hydrolysis of the substrate.<ref name = "Queenan">{{cite journal | vauthors = Queenan AM, Bush K | title = Carbapenemases: the versatile beta-lactamases | journal = Clinical Microbiology Reviews | volume = 20 | issue = 3 | pages = 440–58, table of contents | date = July 2007 | pmid = 17630334 | pmc = 1932750 | doi = 10.1128/CMR.00001-07 }}</ref> Serine carbapenemase-catalyzed hydrolysis employs a three-step [[Mechanism of action|mechanism]] featuring [[acylation]] and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral [[transition state]].<ref name = "Queenan" /><ref name = "Brasseur">{{cite journal | vauthors = Lamotte-Brasseur J, Knox J, Kelly JA, Charlier P, Fonzé E, Dideberg O, Frére JM | title = The structures and catalytic mechanisms of active-site serine beta-lactamases | journal = Biotechnology & Genetic Engineering Reviews | volume = 12 | issue = 1 | pages = 189–230 | date = December 1994 | pmid = 7727028 | doi = 10.1080/02648725.1994.10647912 }}</ref> |
Carbapenemases can be broadly divided into two different categories based on the mechanism they use to [[Hydrolysis|hydrolyze]] the [[lactam]] ring in their [[Substrate (chemistry)|substrates]]: Metallo-β-lactamases contain bound [[zinc]] ions in their active sites and are therefore inhibited by chelating agents like [[Ethylenediaminetetraacetic acid|EDTA]], while [[serine]] carbapenemases feature an [[active site]] [[serine]] that participates in the hydrolysis of the substrate.<ref name = "Queenan">{{cite journal | vauthors = Queenan AM, Bush K | title = Carbapenemases: the versatile beta-lactamases | journal = Clinical Microbiology Reviews | volume = 20 | issue = 3 | pages = 440–58, table of contents | date = July 2007 | pmid = 17630334 | pmc = 1932750 | doi = 10.1128/CMR.00001-07 }}</ref> Serine carbapenemase-catalyzed hydrolysis employs a three-step [[Mechanism of action|mechanism]] featuring [[acylation]] and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral [[transition state]].<ref name = "Queenan" /><ref name = "Brasseur">{{cite journal | vauthors = Lamotte-Brasseur J, Knox J, Kelly JA, Charlier P, Fonzé E, Dideberg O, Frére JM | title = The structures and catalytic mechanisms of active-site serine beta-lactamases | journal = Biotechnology & Genetic Engineering Reviews | volume = 12 | issue = 1 | pages = 189–230 | date = December 1994 | pmid = 7727028 | doi = 10.1080/02648725.1994.10647912 | doi-access = free }}</ref> |
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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]] have previously been investigated or developed as inhibitors of various human proteases.<ref name = "Hecker" /> Vaborbactam, however, is a highly specific β-lactamase inhibitor, with an [[IC50|IC<sub>50</sub>]] >> 1 mM against all human serine hydrolases against which it has been tested.<ref name = "Hecker" /> 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.<ref name = "Griffith">{{cite journal | vauthors = Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN | title = Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects | journal = Antimicrobial Agents and Chemotherapy | volume = 60 | issue = 10 | pages = 6326–32 | date = October 2016 | pmid = 27527080 | pmc = 5038296 | doi = 10.1128/AAC.00568-16 }}</ref> Hecker et al. argue this specificity results from the higher affinity of human [[proteases]] to linear molecules; thus it is expected that a [[boron]] [[heterocycle]] will have zero effect on them. |
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]] have previously been investigated or developed as inhibitors of various human proteases.<ref name = "Hecker" /> Vaborbactam, however, is a highly specific β-lactamase inhibitor, with an [[IC50|IC<sub>50</sub>]] >> 1 mM against all human serine hydrolases against which it has been tested.<ref name = "Hecker" /> 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.<ref name = "Griffith">{{cite journal | vauthors = Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN | title = Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects | journal = Antimicrobial Agents and Chemotherapy | volume = 60 | issue = 10 | pages = 6326–32 | date = October 2016 | pmid = 27527080 | pmc = 5038296 | doi = 10.1128/AAC.00568-16 }}</ref> Hecker et al. argue this specificity results from the higher affinity of human [[proteases]] to linear molecules; thus it is expected that a [[boron]] [[heterocycle]] will have zero effect on them. |
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[[Category:Carboxylic acids]] |
[[Category:Carboxylic acids]] |
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[[Category:Thiophenes]] |
[[Category:Thiophenes]] |
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[[Category: |
[[Category:Boronate esters]] |
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Latest revision as of 08:04, 11 October 2023
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| Routes of administration | IV |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.235.136 |
| Chemical and physical data | |
| Formula | C12H16BNO5S |
| Molar mass | 297.13 g·mol−1 |
| 3D model (JSmol) | |
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Vaborbactam (INN)[1] 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.[2]
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.[3]
Biochemistry
[edit]Vaborbactam is a boronic acid β-lactamase inhibitor with a high affinity for serine β-lactamases, including Klebsiella pneumoniae carbapenemase (KPC).[4] 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.[2]
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.[5] Serine carbapenemase-catalyzed hydrolysis employs a three-step mechanism featuring acylation and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral transition state.[5][6]
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 have previously been investigated or developed as inhibitors of various human proteases.[2] 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.[2] 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.[7] Hecker et al. argue this specificity results from the higher affinity of human proteases to linear molecules; thus it is expected that a boron heterocycle will have zero effect on them.
References
[edit]- ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 75" (PDF). World Health Organization. pp. 161–2. Archived from the original (PDF) on February 2, 2017.
- ^ a b c d Hecker SJ, Reddy KR, Totrov M, Hirst GC, Lomovskaya O, Griffith DC, et al. (May 2015). "Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases". Journal of Medicinal Chemistry. 58 (9): 3682–92. doi:10.1021/acs.jmedchem.5b00127. PMID 25782055.
- ^ "FDA approves new antibacterial drug" (Press release). Food and Drug Administration. August 29, 2017.
- ^ Burgos RM, Biagi MJ, Rodvold KA, Danziger LH (October 2018). "Pharmacokinetic evaluation of meropenem and vaborbactam for the treatment of urinary tract infection". Expert Opinion on Drug Metabolism & Toxicology. 14 (10): 1007–1021. doi:10.1080/17425255.2018.1511702. PMID 30106599. S2CID 52006261.
- ^ a b Queenan AM, Bush K (July 2007). "Carbapenemases: the versatile beta-lactamases". Clinical Microbiology Reviews. 20 (3): 440–58, table of contents. doi:10.1128/CMR.00001-07. PMC 1932750. PMID 17630334.
- ^ Lamotte-Brasseur J, Knox J, Kelly JA, Charlier P, Fonzé E, Dideberg O, Frére JM (December 1994). "The structures and catalytic mechanisms of active-site serine beta-lactamases". Biotechnology & Genetic Engineering Reviews. 12 (1): 189–230. doi:10.1080/02648725.1994.10647912. PMID 7727028.
- ^ Griffith DC, Loutit JS, Morgan EE, Durso S, Dudley MN (October 2016). "Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects". Antimicrobial Agents and Chemotherapy. 60 (10): 6326–32. doi:10.1128/AAC.00568-16. PMC 5038296. PMID 27527080.