D-cycloserine
Overview
Description
- Structurally, cycloserine resembles the amino acid D-alanine . Its mechanism of action involves interfering with the formation of bacterial cell walls, making it effective against certain strains of TB bacteria .
Cycloserine: (chemical formula: C₃H₆N₂O₂) is an antibiotic used primarily in the treatment of tuberculosis (TB). It is also known by its brand name .
Mechanism of Action
Target of Action
Cycloserine, a broad-spectrum antibiotic, primarily targets two crucial enzymes involved in bacterial cell wall synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl) . These enzymes play a critical role in the formation of peptidoglycans, which are essential components of the bacterial cell wall .
Mode of Action
Cycloserine is an analog of the amino acid D-alanine . It interferes with an early step in bacterial cell wall synthesis in the cytoplasm by competitively inhibiting the enzymes Alr and Ddl . Alr is responsible for the conversion of L-alanine to D-alanine, while Ddl incorporates D-alanine into the pentapeptide necessary for peptidoglycan formation .
Biochemical Pathways
The inhibition of Alr and Ddl disrupts the cytosolic stages of peptidoglycan synthesis, a key biochemical pathway in bacteria . This disruption affects the formation of the bacterial cell wall, leading to downstream effects such as weakening of the bacterial cell wall .
Pharmacokinetics
Cycloserine exhibits a bioavailability of approximately 70% to 90% . It is metabolized in the liver and has an elimination half-life of about 10 hours in individuals with normal kidney function . The drug is primarily excreted by the kidneys .
Result of Action
The action of cycloserine results in the inhibition of cell-wall synthesis in susceptible strains of gram-positive and gram-negative bacteria . By blocking the formation of peptidoglycans, the walls of the bacteria become weak, which can lead to the death of the bacteria .
Action Environment
The efficacy and stability of cycloserine can be influenced by various environmental factors. For instance, the drug’s bactericidal or bacteriostatic activity may depend on its concentration at the site of infection and the susceptibility of the organism . Additionally, factors such as the patient’s kidney function can impact the drug’s elimination rate . It’s also worth noting that co-administration of pyridoxine can reduce some of the central nervous system side effects caused by cycloserine .
Biochemical Analysis
Biochemical Properties
Cycloserine plays a crucial role in inhibiting cell-wall biosynthesis in bacteria. It acts as a competitive inhibitor of two key enzymes: alanine racemase and D-alanine:D-alanine ligase. Alanine racemase converts L-alanine to D-alanine, while D-alanine:D-alanine ligase incorporates D-alanine into the pentapeptide necessary for peptidoglycan formation. By inhibiting these enzymes, cycloserine disrupts the formation of the bacterial cell wall, leading to bacterial death .
Cellular Effects
Cycloserine affects various types of cells and cellular processes. It interferes with the formation of the bacterial cell wall, causing the bacteria to become weak and eventually die. This disruption in cell wall synthesis leads to the leakage of cell contents and arrest of further bacterial growth. Additionally, cycloserine’s ability to penetrate the central nervous system can result in neurological side effects such as headaches, dizziness, and confusion .
Molecular Mechanism
At the molecular level, cycloserine exerts its effects by binding to and inhibiting alanine racemase and D-alanine:D-alanine ligase. These enzymes are essential for the synthesis of peptidoglycan, a critical component of the bacterial cell wall. By inhibiting these enzymes, cycloserine prevents the formation of the cell wall, leading to bacterial death. This mechanism of action makes cycloserine an effective antibiotic against drug-resistant strains of tuberculosis .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of cycloserine have been observed to change over time. Cycloserine is stable under basic conditions, with the greatest stability at pH 11.5. Under mildly acidic conditions, it hydrolyzes to give hydroxylamine and D-serine. Long-term effects of cycloserine on cellular function include its ability to kill extracellular bacilli over a period of 28 days, provided optimal exposures are achieved .
Dosage Effects in Animal Models
The effects of cycloserine vary with different dosages in animal models. High doses of cycloserine can be neurotoxic, leading to symptoms such as drowsiness, confusion, and seizures. In studies, doses of 750 mg twice daily achieved target exposure in lung cavities of 92% of patients, while 500 mg twice daily achieved target exposure in 85% of patients with meningitis. These findings highlight the importance of dosage optimization to balance efficacy and toxicity .
Metabolic Pathways
Cycloserine interferes with an early step in bacterial cell wall synthesis by competitively inhibiting alanine racemase and D-alanine:D-alanine ligase. These enzymes are involved in the formation of D-alanine and its incorporation into the pentapeptide necessary for peptidoglycan formation. By blocking these pathways, cycloserine disrupts bacterial cell wall synthesis and leads to bacterial death .
Transport and Distribution
Cycloserine is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration, with a bioavailability of 70 to 90%. It is distributed throughout the body, including the central nervous system, which contributes to its neurological side effects. Cycloserine is primarily excreted by the kidneys .
Subcellular Localization
Cycloserine’s subcellular localization involves its interaction with enzymes in the cytosol, where it inhibits alanine racemase and D-alanine:D-alanine ligase. These interactions prevent the synthesis of peptidoglycan, a critical component of the bacterial cell wall. Cycloserine’s ability to penetrate the central nervous system also suggests its localization within the brain, contributing to its neurological effects .
Preparation Methods
- Cycloserine can be synthesized through various routes, but one common method involves cyclization of L-serine with hydroxylamine . The reaction yields cycloserine along with water.
- Industrial production methods typically involve fermentation using Streptomyces orchidaceus or related strains .
Chemical Reactions Analysis
- Cycloserine undergoes reactions typical of a cyclic amide:
Oxidation: It can be oxidized to form its corresponding oxazolidinone derivative.
Reduction: Reduction of the oxazolidinone ring can yield the open-chain form.
- Common reagents include oxidizing agents (e.g., hydrogen peroxide ) and reducing agents (e.g., sodium borohydride ).
- Major products depend on reaction conditions and substituents .
Scientific Research Applications
Tuberculosis Treatment: Cycloserine is a second-line drug used against drug-resistant TB strains.
Neurological Disorders: Research explores its potential in anxiety disorders, although evidence remains inconclusive.
Mechanistic Studies: Scientists use cycloserine to study cell wall biosynthesis and peptidoglycan formation.
Comparison with Similar Compounds
- Cycloserine’s uniqueness lies in its cyclic structure and specific mechanism of action.
- Similar compounds include other antibiotics targeting cell wall synthesis, such as penicillins and cephalosporins .
Properties
IUPAC Name |
(4R)-4-amino-1,2-oxazolidin-3-one |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
DYDCUQKUCUHJBH-UWTATZPHSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1C(C(=O)NO1)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Isomeric SMILES |
C1[C@H](C(=O)NO1)N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C3H6N2O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID8022870 |
Source
|
| Record name | Cycloserine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID8022870 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
102.09 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Cycloserine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014405 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Solubility |
Soluble, SOL IN WATER; SLIGHTLY SOL IN METHANOL, PROPYLENE GLYCOL, 8.77e+02 g/L |
Source
|
| Record name | Cycloserine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00260 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
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| Record name | CYCLOSERINE | |
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| Record name | Cycloserine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014405 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Cycloserine is an analog of the amino acid D-alanine. It interferes with an early step in bacterial cell wall synthesis in the cytoplasm by competitive inhibition of two enzymes, L-alanine racemase, which forms D-alanine from L-alanine, and D-alanylalanine synthetase, which incorporates D-alanine into the pentapeptide necessary for peptidoglycan formation and bacterial cell wall synthesis., EXCRETION OF B-ALANINE & D-BETA-AMINOISOBUTYRIC ACID WAS INCR IN PT WITH TUBERCULOSIS RECEIVING CLINICAL DOSES OF D-CYCLOSERINE., Cycloserine is inhibitory for Mycobacterium tuberculosis in concentrations of 5 to 20 ug/ml in vitro. There is no cross-resistance between cycloserine and other tuberculostatic agents. While the antibiotic is effective in experimental infections caused by other microorganisms, studies in vitro reveal no suppression of growth in cultures made in conventional media, which contain D-alanine; this amino acid blocks the antibacterial activity of cycloserine. ... Cycloserine inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis. The use of media free of D-alanine reveals that the antibiotic inhibits the growth in vitro of enterococci, E. coli, Staph. aureus, Nocardia species, and Chlamydia. |
Source
|
| Record name | Cycloserine | |
| Source | DrugBank | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3218 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
CRYSTALS, WHITE TO PALE YELLOW, CRYSTALLINE POWDER | |
CAS No. |
68-41-7 |
Source
|
| Record name | (+)-Cycloserine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=68-41-7 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
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| Record name | Cycloserine [USP:INN:BAN:JAN] | |
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| Record name | Cycloserine | |
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| URL | https://www.drugbank.ca/drugs/DB00260 | |
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| Record name | Cycloserine | |
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| Record name | Cycloserine | |
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| Record name | CYCLOSERINE | |
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| Record name | Cycloserine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014405 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Melting Point |
155-156 °C (decomposes), 147 °C |
Source
|
| Record name | Cycloserine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00260 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
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| Record name | CYCLOSERINE | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/3218 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
| Record name | Cycloserine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0014405 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
Q1: What is the primary mechanism of action of D-Cycloserine?
A1: this compound acts as a partial agonist at the glycine recognition site of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. [] This interaction enhances extinction learning, a key process in exposure therapy for anxiety disorders. []
Q2: Does this compound impact neuronal excitability?
A2: Yes, this compound has been shown to enhance both intrinsic excitability of CA1 hippocampal neurons and expression of activity-regulated cytoskeletal (Arc) protein, likely via modulation of Ca2+-dependent K+ conductances. [] This increased excitability is observed as a decrease in the duration and area of post-burst afterhyperpolarizations (AHPs). []
Q3: How does L-Cycloserine differ in its mechanism of action compared to this compound?
A3: While this compound acts on NMDA receptors, L-Cycloserine primarily inhibits serine palmitoyltransferase (SPT), the enzyme catalyzing the first step in sphingolipid biosynthesis. [] This inhibition makes L-Cycloserine a potential substrate reduction therapy agent for diseases like Krabbe disease. []
Q4: What is the molecular formula and weight of Cycloserine?
A4: Cycloserine (C4H6N2O2) has a molecular weight of 102.1 g/mol.
Q5: What are the structural features of Cycloserine that contribute to its activity?
A5: Cycloserine, a cyclic analog of D-alanine, exhibits its inhibitory action due to its structural similarity to D-alanine, allowing it to compete for binding sites on enzymes like alanine racemase. [] The specific conformation of this compound, as opposed to L-Cycloserine, is crucial for its interaction with alanine racemase. []
Q6: How does the stability of Cycloserine change in different environments?
A6: Cycloserine displays sensitivity to various factors affecting its stability. Research shows that composite particles composed of Cycloserine and calcium hydroxide exhibit improved stability under accelerated stress conditions (60°C/75% RH for 24 hours) compared to Cycloserine alone. [] This finding highlights the potential of excipients like calcium hydroxide to enhance Cycloserine's stability in pharmaceutical formulations.
Q7: What strategies can be employed to improve the stability of Cycloserine formulations?
A7: One strategy involves the use of inorganic compounds like calcium hydroxide to create composite particles with Cycloserine. [] This approach, as demonstrated in a study, significantly enhanced the drug's stability under accelerated stress conditions. [] The compatibility between Cycloserine and calcium hydroxide was confirmed using differential scanning calorimetry. []
Q8: What is the pharmacokinetic profile of Cycloserine?
A8: Cycloserine is rapidly absorbed after oral administration, achieving peak plasma concentrations within 4 hours. [, ] It is widely distributed throughout the body, including the cerebrospinal fluid, and is primarily excreted unchanged in the urine. [, ] Notably, Cycloserine exhibits significant interindividual pharmacokinetic variability, influenced by factors such as food intake and drug interactions. []
Q9: What are the potential benefits of therapeutic drug monitoring for Cycloserine?
A9: Due to its narrow therapeutic index and interindividual pharmacokinetic variability, therapeutic drug monitoring of Cycloserine blood levels is crucial to ensure efficacy and minimize the risk of toxicity, particularly neurotoxicity. [, ] Maintaining blood levels within the therapeutic range (20-40 μg/mL) has been associated with improved treatment outcomes and reduced toxicity. []
Q10: Are there specific drug-metabolizing enzymes involved in Cycloserine metabolism?
A10: There is limited information available on the specific drug-metabolizing enzymes involved in Cycloserine metabolism. Further research is needed to determine if Cycloserine induces or inhibits drug-metabolizing enzymes and if this contributes to drug interactions or variability in patient response.
Q11: What animal models have been used to study Cycloserine?
A11: Researchers have employed various animal models to investigate the effects of Cycloserine. Studies in rats have explored its potential in treating Parkinson's disease, where long-term treatment with low-dose Cycloserine showed promise in reducing motor disturbances. [] Additionally, twitcher mice, a model for Krabbe disease, have been used to study the therapeutic potential of L-Cycloserine as a substrate reduction therapy. []
Q12: How effective is this compound as an adjunct therapy for anxiety and PTSD?
A12: While initial studies showed promise, larger and more recent studies, including those with patients suffering from social anxiety disorder, post-traumatic stress disorder, and OCD, have shown less promising and sometimes even detrimental results for using this compound as an adjunct therapy. [, , , , ]
Q13: How does resistance to Cycloserine develop in bacteria?
A13: Resistance to Cycloserine in bacteria like Mycobacterium tuberculosis can develop through mutations in the alr gene encoding alanine racemase, the primary target of Cycloserine. [, ] These mutations can alter the enzyme's structure, reducing Cycloserine's binding affinity and its ability to inhibit the enzyme's activity. [, ]
Q14: Are there any known instances of cross-resistance between Cycloserine and other antibiotics?
A14: While cross-resistance between Cycloserine and other antibiotics is not commonly reported, a study investigating Salmonella Typhimurium mutants deficient in cytochrome bd oxidase showed increased resistance to various antibiotics, including this compound, aminoglycosides, and ampicillin. [] This finding suggests potential links between bacterial respiratory pathways and susceptibility to this compound. []
Q15: What are the known toxicological effects of Cycloserine?
A15: Cycloserine is associated with a range of neuropsychiatric side effects, including seizures, depression, psychosis, and suicidal ideation. [, , , , , , , , ] These side effects are dose-dependent and can be severe, sometimes leading to treatment discontinuation. [, , , , ] Patients with a history of psychiatric disorders might be particularly vulnerable to these adverse effects. [, ]
Q16: Are there any specific populations where Cycloserine use requires extra caution due to potential toxicity?
A16: Cycloserine should be used with extreme caution in patients with pre-existing psychiatric conditions, as it can exacerbate symptoms and increase the risk of suicidal thoughts and behaviors. [, , ] Careful monitoring and alternative treatment options should be considered for this patient population.
Q17: Are there strategies being explored to improve the delivery of Cycloserine to specific targets?
A17: One approach to enhance Cycloserine's delivery across biological barriers, such as the skin, involves the synthesis of 4,5-dihydroisoxazol-3-yl fatty acid ester derivatives. [] These derivatives demonstrate improved skin permeation compared to Cycloserine itself, highlighting their potential as topical prodrugs for skin infections. []
Q18: What analytical methods are used to quantify Cycloserine levels?
A18: Various analytical methods are used to quantify Cycloserine, including colorimetric assays, high-performance liquid chromatography (HPLC), and second-derivative UV spectrophotometry. [, ] The choice of method depends on the specific application and required sensitivity. For instance, HPLC methods coupled with fluorometric detection using labeling agents like 9-chloro-10-methyl acridinium triflate offer high sensitivity for quantifying Cycloserine in biological samples, including urine. []
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