Amdinocillin

Targets (6)Biointeractions (6)

Identification

Name
Amdinocillin
Accession Number
DB01163  (APRD00789)
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

Amidinopenicillanic acid derivative with broad spectrum antibacterial action. It is poorly absorbed if given orally and is used in urinary infections and typhus. Amdinocillin is not available in the United States.

Structure
Thumb
3D
Similar Structures
Synonyms
  • Mecillinam
  • Penicillin HX
International/Other Brands
Coactin / Selexid (Leo)
Categories
UNII
V10579P3QZ
CAS number
32887-01-7
Weight
Average: 325.426
Monoisotopic: 325.146012307
Chemical Formula
C15H23N3O3S
InChI Key
BWWVAEOLVKTZFQ-ISVUSNJMSA-N
InChI
InChI=1S/C15H23N3O3S/c1-15(2)11(14(20)21)18-12(19)10(13(18)22-15)16-9-17-7-5-3-4-6-8-17/h9-11,13H,3-8H2,1-2H3,(H,20,21)/b16-9+/t10-,11+,13-/m1/s1
IUPAC Name
(2S,5R,6R)-6-[(azepan-1-ylmethylidene)amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
SMILES
[H]C(=N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@]12[H])N1CCCCCC1

Pharmacology

Indication

Used in the treatment of urinary tract infections caused by some strains of E. coli and klebsiella and enterobacter species. Used mainly against Gram negative organisms.

Pharmacodynamics

Amdinocillin is a novel, semisynthetic penicillin effective against many gram-negative bacteria. The antibacterial activity of amdinocillin is derived from its ability to bind specifically and avidly to Penicillin Binding Protein-2 (PBP 2). Amdinocillin is active alone against many gram-negative organisms. Pseudomonas and non-fermenting gram-negative bacteria, however, are usually resistant. Amdinocillin, in combination with many beta-lactams, exhibits marked synergy against many enterobacteriaceae. No such synergy can be demonstrated for gram-positive organisms or pseudomonas species. Amdinocillin is not beta-lactamase stable. Organisms which produce high levels of plasma-mediated beta-lactamase are resistant to the drug. Co-administration of probenecid results in markedly elevated plasma levels of amdinocillin and delays its excretion.

Mechanism of action

Amdinocillin is a stong and specific antagonist of Penicillin Binding Protein-2 (PBP 2). It is active against gram negative bacteria, preventing cell wall synthesis by inhibiting the activity of PBP2. PBP2 is a peptidoglycan elongation initiating enzyme. Peptidoglycan is a polymer of sugars and amino acids that is the main component of bacterial cell walls.

TargetActionsOrganism
APenicillin-binding protein 2a
inhibitor
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
APenicillin-binding protein 2
inhibitor
Escherichia coli (strain K12)
APenicillin-binding protein 3
inhibitor
Streptococcus pneumoniae
APenicillin-binding protein 1A
inhibitor
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
APenicillin-binding protein 2B
inhibitor
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
APenicillin-binding protein 1b
inhibitor
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Absorption

Poorly absorbed if given orally.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Approximately 1 hour in patients with normal renal function. Increases to 3 to 6 hours in anephric patients.

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Gram-negative Bacteria
  • Staphylococcus saprophyticus
  • Escherichia coli
  • Proteus mirabilis
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcenocoumarolAmdinocillin may increase the anticoagulant activities of Acenocoumarol.
AmikacinThe serum concentration of Amikacin can be decreased when it is combined with Amdinocillin.
ApramycinThe serum concentration of Apramycin can be decreased when it is combined with Amdinocillin.
ArbekacinThe serum concentration of Arbekacin can be decreased when it is combined with Amdinocillin.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Amdinocillin.
BekanamycinThe serum concentration of Bekanamycin can be decreased when it is combined with Amdinocillin.
CapreomycinThe serum concentration of Capreomycin can be decreased when it is combined with Amdinocillin.
ChlortetracyclineThe therapeutic efficacy of Amdinocillin can be decreased when used in combination with Chlortetracycline.
ClorindioneAmdinocillin may increase the anticoagulant activities of Clorindione.
DemeclocyclineThe therapeutic efficacy of Amdinocillin can be decreased when used in combination with Demeclocycline.
Food Interactions
Not Available

References

Synthesis Reference

U.S. Patent 3,957,764.

General References
  1. Neu HC: Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. Am J Med. 1983 Aug 29;75(2A):9-20. [PubMed:6311012]
External Links
KEGG Drug
D02888
PubChem Compound
36273
PubChem Substance
46508450
ChemSpider
33357
ChEBI
51208
ChEMBL
CHEMBL530
Therapeutic Targets Database
DAP001176
PharmGKB
PA164754807
Wikipedia
Amdinocillin
ATC Codes
J01CA11 — Mecillinam
MSDS
Download (42.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Cystitis (Excl in Pregnancy)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)156 dec °CPhysProp
water solubility0.0103 mg/mL at 25 °CMEYLAN,WM et al. (1996)
logP1.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.979 mg/mLALOGPS
logP1.41ALOGPS
logP-0.55ChemAxon
logS-2.5ALOGPS
pKa (Strongest Acidic)3.3ChemAxon
pKa (Strongest Basic)7.92ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area73.21 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity84.31 m3·mol-1ChemAxon
Polarizability34.18 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.8439
Blood Brain Barrier-0.9659
Caco-2 permeable-0.6287
P-glycoprotein substrateSubstrate0.7402
P-glycoprotein inhibitor INon-inhibitor0.6666
P-glycoprotein inhibitor IINon-inhibitor0.9677
Renal organic cation transporterNon-inhibitor0.7438
CYP450 2C9 substrateNon-substrate0.7291
CYP450 2D6 substrateNon-substrate0.779
CYP450 3A4 substrateSubstrate0.5355
CYP450 1A2 substrateNon-inhibitor0.8467
CYP450 2C9 inhibitorNon-inhibitor0.8666
CYP450 2D6 inhibitorNon-inhibitor0.9033
CYP450 2C19 inhibitorNon-inhibitor0.7809
CYP450 3A4 inhibitorNon-inhibitor0.8914
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9761
Ames testNon AMES toxic0.7016
CarcinogenicityNon-carcinogens0.8428
BiodegradationNot ready biodegradable0.5648
Rat acute toxicity1.5443 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9958
hERG inhibition (predictor II)Non-inhibitor0.7974
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-0209000000-8ccc98a85688a2a0d3da

Taxonomy

Description
This compound belongs to the class of organic compounds known as alpha amino acids and derivatives. These are amino acids in which the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (alpha carbon), or a derivative thereof.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acids and derivatives
Alternative Parents
Penams / Azepanes / Thiazolidines / Tertiary carboxylic acid amides / Azetidines / Azacyclic compounds / Thiohemiaminal derivatives / Propargyl-type 1,3-dipolar organic compounds / Carboxamidines / Monocarboxylic acids and derivatives
show 8 more
Substituents
Alpha-amino acid or derivatives / Penam / Azepane / Beta-lactam / Tertiary carboxylic acid amide / Thiazolidine / Azetidine / Carboxamide group / Lactam / Amidine
show 21 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
penicillin (CHEBI:51208)

Targets

Details1. Penicillin-binding protein 2a
Kind
Protein
Organism
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transferase activity, transferring acyl groups
Specific Function
Not Available
Gene Name
pbp2a
Uniprot ID
Q8DNB6
Uniprot Name
Penicillin-binding protein 2a
Molecular Weight
80797.94 Da
References
  1. Williamson R, Hakenbeck R, Tomasz A: In vivo interaction of beta-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980 Oct;18(4):629-37. [PubMed:7447421]
Details2. Penicillin-binding protein 2
Kind
Protein
Organism
Escherichia coli (strain K12)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function
Cell wall formation; PBP-2 is responsible for the determination of the rod shape of the cell. It synthesizes cross-linked peptidoglycan from lipid intermediates.
Gene Name
mrdA
Uniprot ID
P0AD65
Uniprot Name
Penicillin-binding protein 2
Molecular Weight
70856.1 Da
References
  1. Neu HC: Penicillin-binding proteins and role of amdinocillin in causing bacterial cell death. Am J Med. 1983 Aug 29;75(2A):9-20. [PubMed:6311012]
  2. Licht J, Gally D, Henderson T, Young K, Cooper S: Effect of mecillinam on peptidoglycan synthesis during the division cycle of Salmonella typhimurium 2616. Res Microbiol. 1993 Jul-Aug;144(6):423-33. [PubMed:8190989]
Details3. Penicillin-binding protein 3
Kind
Protein
Organism
Streptococcus pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function
Not Available
Gene Name
pbp3
Uniprot ID
Q75Y35
Uniprot Name
Penicillin-binding protein 3
Molecular Weight
45209.84 Da
References
  1. Williamson R, Hakenbeck R, Tomasz A: In vivo interaction of beta-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980 Oct;18(4):629-37. [PubMed:7447421]
Details4. Penicillin-binding protein 1A
Kind
Protein
Organism
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Penicillin binding
Specific Function
Cell wall formation.
Gene Name
pbpA
Uniprot ID
Q8DR59
Uniprot Name
Penicillin-binding protein 1A
Molecular Weight
79700.9 Da
References
  1. Williamson R, Hakenbeck R, Tomasz A: In vivo interaction of beta-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980 Oct;18(4):629-37. [PubMed:7447421]
Details5. Penicillin-binding protein 2B
Kind
Protein
Organism
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Not Available
Specific Function
Penicillin binding
Gene Name
penA
Uniprot ID
P0A3M6
Uniprot Name
Penicillin-binding protein 2B
Molecular Weight
73872.305 Da
References
  1. Williamson R, Hakenbeck R, Tomasz A: In vivo interaction of beta-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980 Oct;18(4):629-37. [PubMed:7447421]
Details6. Penicillin-binding protein 1b
Kind
Protein
Organism
Streptococcus pneumoniae (strain ATCC BAA-255 / R6)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transferase activity, transferring acyl groups
Specific Function
Not Available
Gene Name
pbp1b
Uniprot ID
Q7CRA4
Uniprot Name
Penicillin-binding protein 1b
Molecular Weight
89479.92 Da
References
  1. Williamson R, Hakenbeck R, Tomasz A: In vivo interaction of beta-lactam antibiotics with the penicillin-binding proteins of Streptococcus pneumoniae. Antimicrob Agents Chemother. 1980 Oct;18(4):629-37. [PubMed:7447421]

Drug created on June 13, 2005 07:24 / Updated on October 01, 2018 13:00