Identification

Name
Plazomicin
Accession Number
DB12615
Type
Small Molecule
Groups
Approved, Investigational
Description

Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from Sisomicin. The structure of plazomicin was established via appending hydroxylaminobutyric acid to Sisomicin at position 1 and 2-hydroxyethyl group at position 6' [1]. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy [1]. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations [1]. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases [Label]. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis [Label]. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.

Structure
Thumb
Synonyms
Not Available
External IDs
ACHN 490 / ACHN-490 / ACHN490
Product Ingredients
IngredientUNIICASInChI Key
Plazomicin sulfateA78L6MT7461380078-95-4SFTBRKHJMASSAP-BGJNVEJLSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Zemdri (plazomicin)Injection500 mg/10mLIntravenousAchaogen, Inc.2018-07-16Not applicableUs
Categories
UNII
LYO9XZ250J
CAS number
1154757-24-0
Weight
Average: 592.691
Monoisotopic: 592.34319177
Chemical Formula
C25H48N6O10
InChI Key
IYDYFVUFSPQPPV-PEXOCOHZSA-N
InChI
InChI=1S/C25H48N6O10/c1-25(37)11-38-24(18(35)21(25)29-2)41-20-15(31-22(36)16(33)5-6-26)9-14(28)19(17(20)34)40-23-13(27)4-3-12(39-23)10-30-7-8-32/h3,13-21,23-24,29-30,32-35,37H,4-11,26-28H2,1-2H3,(H,31,36)/t13-,14+,15-,16+,17+,18-,19-,20+,21-,23-,24-,25+/m1/s1
IUPAC Name
(2S)-4-amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-{[(2S,3R)-3-amino-6-{[(2-hydroxyethyl)amino]methyl}-3,4-dihydro-2H-pyran-2-yl]oxy}-2-{[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)oxan-2-yl]oxy}-3-hydroxycyclohexyl]-2-hydroxybutanamide
SMILES
CN[C@@H]1[C@@H](O)[C@@H](O[C@H]2[C@@H](C[C@H](N)[C@@H](O[C@H]3OC(CNCCO)=CC[C@H]3N)[C@@H]2O)NC(=O)[C@@H](O)CCN)OC[C@]1(C)O

Pharmacology

Indication

Plazomicin is indicated for the treatment of patients 18 years of age or older with Complicated Urinary Tract Infections (cUTI) including Pyelonephritis, who have limited or no alternative treatment options. It should only be used to treat infections that are proven or strongly suspected to be caused by susceptible microorganisms [Label].

Associated Conditions
Pharmacodynamics

Plazomicin exerts its antibacterial activity in a dose-dependent manner with a post-antibiotic effect ranging from 0.2 to 2.6 hours at 2X MIC against Enterobacteriaceae, as demonstrated by in vitro studies [Label]. In clinical trials comprising of hospitalized adult patients with cUTI (including pyelonephritis), resolution or improvement of clinical cUTI symptoms and a microbiological outcome of eradication were observed at day 5 following the first dose administration of plazomicin [Label]. Plazomicin has shown to elicit nephrotoxic, ototoxic, and neuromuscular blocking effects. In clinical trials, it did not induce any clinically relevant QTc-prolonging effects [Label].

Mechanism of action

Plazomicin exerts a bactericidal action against susceptible bacteria by binding to bacterial 30S ribosomal subunit [1]. Aminoglycosides typically bind to the ribosomal aminoacyl-tRNA site (A-site) and induce a conformational change to further facilitate the binding between the rRNA and the antibiotic [5]. This leads to codon misreading and mistranslation of mRNA during bacterial protein synthesis [5].

Plazomicin demonstrates potency against Enterobacteriaceae, including species with multidrug-resistant phenotypes such as carbapenemase-producing bacteria and isolates with resistance to all other aminoglycosides [1, 2, 3]. Its antibacterial activity is not inhibited by aminoglycoside modifying enzymes (AMEs) produced by bacteria, such as acetyltransferases (AACs), phosphotransferases (APHs), and nucleotidyltransferases (ANTs) [4]. Plazomicin was shown to be effective against Enterobacteriaceae in presence of some beta-lactamases [Label]. In clinical settings and in vivo, bacteria shown to be susceptible toward plazomicin include Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae [Label]. Other aerobic bacteria that may be affected by plazomicin are Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Klebsiella oxytoca, Morganella morganii, Proteus vulgaris, Providencia stuartii, and Serratia marcescens [Label].

TargetActionsOrganism
U30S ribosomal protein S14
inhibitor
Escherichia coli (strain K12)
A30S ribosomal protein S11
inhibitor
Enterobacteriaceae bacterium (strain FGI 57)
Absorption

Administration of 15 mg/kg plazomicin by 30-minute IV infusion resulted in peak plasma concentrations of 73.7 ± 19.7 μg/mL in healthy adult subjects and 51.0 ± 26.7 μg/mL in patients with complicated urinary tract infections (cUTI) [Label]. The area under the curve (AUC) were 257 ± 67.0 μg.h/mL in healthy adults and 226 ± 113 μg.h/mL in cUTI patients [Label].

Volume of distribution

The mean (±SD) volume of distribution is 17.9 (±4.8) L in healthy adults and 30.8 (±12.1) L in cUTI patients [Label].

Protein binding

The extent of plasma protein binding in humans is approximately 20% [Label]. The degree of protein binding was concentration-independent across the range tested in vitro (5 to 100 mcg/mL) [Label].

Metabolism

Plazomicin is not reported to undergo significant metabolism [Label].

Route of elimination

Plazomicin predominantly undergoes renal excretion, where 56% of the total administered drug was recovered in the urine within 4 hours following a single 15 mg/kg IV dose of radiolabeled plazomicin in healthy subjects. About less than 0.2% and 89.1% of the total drug were recovered within 168 hours in feces and urine, respectively [Label].

Half life

The mean (±SD) half-life of plazomicin was 3.5 h (±0.5) in healthy adults with normal renal function receiving 15 mg/kg plazomicin via intravenous infusion [Label].

Clearance

Following administration of 15 mg/kg plazomicin by 30-minute IV infusion, the mean (±SD) total body clearance in healthy adults and cUTI patients is 4.5 (±0.9) and 5.1 (±2.01) L/h, respectively [Label].

Toxicity

In case of suspected overdose, plazomicin therapy should be discontinued with initiation of supportive care. Maintenance of glomerular filtration and careful monitoring of renal function is recommended. Hemodialysis may be used to facilitate drug elimination, and this may be especially clinically useful in patients with compromised renal function [Label].

Affected organisms
  • Pseudomonas aeruginosa
  • Escherichia coli
  • Acinetobacter
  • Enterobacter
  • Klebsiella pneumoniae
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limonene(4R)-limonene may decrease the excretion rate of Plazomicin which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Plazomicin which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Plazomicin which could result in a higher serum level.
AcetaminophenPlazomicin may decrease the excretion rate of Acetaminophen which could result in a higher serum level.
AcetyldigitoxinThe serum concentration of Acetyldigitoxin can be decreased when it is combined with Plazomicin.
AcetyldigoxinThe serum concentration of Acetyldigoxin can be decreased when it is combined with Plazomicin.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Plazomicin which could result in a higher serum level.
AlclofenacAlclofenac may decrease the excretion rate of Plazomicin which could result in a higher serum level.
AlcuroniumPlazomicin may increase the respiratory depressant activities of Alcuronium.
Alendronic acidPlazomicin may increase the hypocalcemic activities of Alendronic acid.
Food Interactions
Not Available

References

General References
  1. Karaiskos I, Souli M, Giamarellou H: Plazomicin: an investigational therapy for the treatment of urinary tract infections. Expert Opin Investig Drugs. 2015;24(11):1501-11. doi: 10.1517/13543784.2015.1095180. Epub 2015 Sep 30. [PubMed:26419762]
  2. Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P: Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017 Oct 1;72(10):2787-2791. doi: 10.1093/jac/dkx239. [PubMed:29091226]
  3. Zhang Y, Kashikar A, Bush K: In vitro activity of plazomicin against beta-lactamase-producing carbapenem-resistant Enterobacteriaceae (CRE). J Antimicrob Chemother. 2017 Oct 1;72(10):2792-2795. doi: 10.1093/jac/dkx261. [PubMed:29091224]
  4. Lopez-Diaz MD, Culebras E, Rodriguez-Avial I, Rios E, Vinuela-Prieto JM, Picazo JJ, Rodriguez-Avial C: Plazomicin Activity against 346 Extended-Spectrum-beta-Lactamase/AmpC-Producing Escherichia coli Urinary Isolates in Relation to Aminoglycoside-Modifying Enzymes. Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: AAC.02454-16. doi: 10.1128/AAC.02454-16. Print 2017 Feb. [PubMed:27919895]
  5. Dlugosz M, Trylska J: Aminoglycoside association pathways with the 30S ribosomal subunit. J Phys Chem B. 2009 May 21;113(20):7322-30. doi: 10.1021/jp8112914. [PubMed:19438282]
External Links
PubChem Compound
42613186
PubChem Substance
347828829
ChemSpider
26390008
ChEMBL
CHEMBL1650559
HET
EDS
Wikipedia
Plazomicin
PDB Entries
6cd7
FDA label
Download (436 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHealthy Volunteers1
1CompletedTreatmentCardiac Effects in Normal Healthy Volunteers1
1CompletedTreatmentHealthy Volunteers2
1CompletedTreatmentImpaired Renal Function1
2CompletedTreatmentAcute Pyelonephritis / Complicated Urinary Tract Infections1
3CompletedTreatmentAcute Pyelonephritis (AP) Due to CRE / Bloodstream Infections (BSI) Due to CRE / Complicated Urinary Tract Infection (cUTI) Due to CRE / Hospital-Acquired Bacterial Pneumonia (HABP) Due to CRE / Ventilator-Associated Bacterial Pneumonia (VABP) Due to CRE1
3CompletedTreatmentAcute Pyelonephritis / Complicated Urinary Tract Infections1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous500 mg/10mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8383596No2011-06-022031-06-02Us
US9688711No2008-11-212028-11-21Us
US9266919No2008-11-212028-11-21Us
US8822424No2008-11-212028-11-21Us

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility12.3 mg/mLALOGPS
logP-2.2ALOGPS
logP-6.1ChemAxon
logS-1.7ALOGPS
pKa (Strongest Acidic)12.48ChemAxon
pKa (Strongest Basic)9.89ChemAxon
Physiological Charge5ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count11ChemAxon
Polar Surface Area269.29 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity145.09 m3·mol-1ChemAxon
Polarizability62.27 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as gamma amino acids and derivatives. These are amino acids having a (-NH2) group attached to the gamma carbon atom.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Gamma amino acids and derivatives
Alternative Parents
O-glycosyl compounds / Aminocyclitols and derivatives / Aminosaccharides / Cyclohexylamines / Cyclohexanols / Oxanes / N-acyl amines / Monosaccharides / Tertiary alcohols / 1,3-aminoalcohols
show 11 more
Substituents
Gamma amino acid or derivatives / Glycosyl compound / O-glycosyl compound / Aminocyclitol or derivatives / Cyclohexanol / Cyclohexylamine / Amino saccharide / Cyclitol or derivatives / Fatty amide / Fatty acyl
show 30 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Structural constituent of ribosome
Specific Function
Binds 16S rRNA, required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site.
Gene Name
rpsN
Uniprot ID
P0AG59
Uniprot Name
30S ribosomal protein S14
Molecular Weight
11580.36 Da
Kind
Protein
Organism
Enterobacteriaceae bacterium (strain FGI 57)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Located on the platform of the 30S subunit, it bridges several disparate RNA helices of the 16S rRNA. Forms part of the Shine-Dalgarno cleft in the 70S ribosome.
Specific Function
Rrna binding
Gene Name
rpsK
Uniprot ID
L0LZJ6
Uniprot Name
30S ribosomal protein S11
Molecular Weight
13858.85 Da
References
  1. Denervaud-Tendon V, Poirel L, Connolly LE, Krause KM, Nordmann P: Plazomicin activity against polymyxin-resistant Enterobacteriaceae, including MCR-1-producing isolates. J Antimicrob Chemother. 2017 Oct 1;72(10):2787-2791. doi: 10.1093/jac/dkx239. [PubMed:29091226]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition of MATE1 renal transporter was observed in vitro with an IC50 value of 1300 mcg/mL.
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Inhibition of MATE2-K renal transporter was observed in vitro with an IC50 value of 338 mcg/mL.
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da

Drug created on October 20, 2016 17:13 / Updated on September 21, 2018 00:19