Cycloserine

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Cycloserine
Cycloserine.svg
Cycloserine ball-and-stick model.png
Clinical data
Trade names Seromycin
Other namesD-cycloserine, 4-amino-3-isoxazolidinone
AHFS/Drugs.com Monograph
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability ~70% to 90%
Metabolism Liver
Elimination half-life 10 hrs (normal kidney function)
Excretion Kidney
Identifiers
  • (R)-4-Amino-1,2-oxazolidin-3-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.626 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C3H6N2O2
Molar mass 102.093 g·mol−1
3D model (JSmol)
Melting point 155 to 156 °C (311 to 313 °F) (dec.)
  • O=C1NOC[C@H]1N
  • InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1 Yes check.svgY
  • Key:DYDCUQKUCUHJBH-UWTATZPHSA-N Yes check.svgY
   (verify)

Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis. [1] [2] Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. [2] It is given by mouth. [2]

Contents

Common side effects include allergic reactions, seizures, sleepiness, unsteadiness, and numbness. [2] It is not recommended in people who have kidney failure, epilepsy, depression, or are alcoholics. [2] It is unclear if use during pregnancy is safe for the baby. [2] Cycloserine is similar in structure to the amino acid D-alanine and works by interfering with the formation of the bacteria's cell wall. [2]

Cycloserine was discovered in 1954 from a type of Streptomyces . [3] It is on the World Health Organization's List of Essential Medicines. [4]

Medical uses

Tuberculosis

For the treatment of tuberculosis, cycloserine is classified as a second-line drug. Its use is only considered if one or more first-line drugs cannot be used. Hence, cycloserine is restricted for use only against multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. Another reason for limited use of this drug is the neurological side effects it causes, since it is able to penetrate into the central nervous system (CNS) and cause headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors). [5] [6] Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures. [6] Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.[ citation needed ]

Psychiatry

A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015. [7] Another review found preliminary evidence of benefit. [8] Evidence for use in addiction is tentative but also unclear. [9]

Mechanism of action

Cycloserine works as an antibiotic by inhibiting cell-wall biosynthesis in bacteria. [10] [11] As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of peptidoglycan synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). [11] The first enzyme is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. [11] The second enzyme is involved in joining two of these D-alanine residues together by catalyzing the formation of the ATP-dependent D-alanine-D-alanine dipeptide bond between the resulting D-alanine molecules. [11] If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined. [11] This effectively leads to inhibition of peptidoglycan synthesis. [11]

Psychiatric use is suggested based on partial NMDA receptor agonism, which improves neural plasticity in lab animals. The degree of clinical usefulness is, as aforementioned, unclear and still being explored, as of 2016. [8]

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine. [12] [13] Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond.[ citation needed ]

Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5. [12]

Synthesis

Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis from DL‐β‐aminoxyalanine ethyl ester. In 1957, Platter et al. managed to synthesis the pure D-enantiomer by cyclizing the corresponding α‐amino‐β‐chlorohydroxamic acids. Chemical synthesis of the compound was revolutionized in the 2010s, when several approaches starting with the cheap D-serine (mirror form of normal L-serine) were published by different groups. [14]

The biosynthesis of the compound is defined by a ten-gene cluster. L-serine and L-arginine are converted to O-ureido-L-serine, flipped to O-ureido-D-serine, then turned into the final compound by cyclization. In 2013, Uda et al. successfully used recombinant versions of three enzymes in the cluster to produce the compound. [15]

A 1963 patent describes industrial production of the drug by bacterial fermentation. [16] It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.[ citation needed ]

History

The compound was first isolated nearly simultaneously by two teams. Workers at Merck isolated the compound, which they called oxamycin, from a species of Streptomyces. [17] The same team prepared the molecule synthetically. [18] Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine. [19]

Economics

In the U.S., the price of cycloserine increased from $500 for 30 pills to $10,800 in 2015 after the Chao Center for Industrial Pharmacy and Contract Manufacturing changed ownership to Rodelis Therapeutics in August 2015. [20]

The price increase was rescinded after the previous owner, the Purdue University Research Foundation, which retained "oversight of the manufacturing operation" intervened and Rodelis returned the drug to an NGO of Purdue University. The foundation now will charge $1,050 for 30 capsules, twice what it charged before". Eli Lilly has been criticised for not ensuring that the philanthropic initiative continued. Due to US antitrust laws, however, no company may control the price of a product after it is outlicensed. [21]

In 2015, the cost in the United States was increased to US$3,150 a month and then decreased to US$1,050 per month. [21]

Research

Reviews in 2016-17 found that cycloserine produced a small improvement in cognitive behavioral therapy for anxiety, obsessive-compulsive disorder, and post-traumatic stress disorder, [22] and had potential for use as a therapy in psychiatric diseases. [8]

Further reading

Related Research Articles

β-Lactam Family of chemical compounds

A β-lactam (beta-lactam) ring is a four-membered lactam. A lactam is a cyclic amide, and beta-lactams are named so because the nitrogen atom is attached to the β-carbon atom relative to the carbonyl. The simplest β-lactam possible is 2-azetidinone. β-lactams are significant structural units of medicines as manifested in many β-lactam antibiotics. Up to 1970, most β-lactam research was concerned with the penicillin and cephalosporin groups, but since then, a wide variety of structures have been described.

Serine is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC.

<span class="mw-page-title-main">Vancomycin</span> Antibiotic medication

Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously to treat complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally to treat Clostridioides difficile infections. When taken orally, it is poorly absorbed.

<span class="mw-page-title-main">Phenelzine</span> Antidepressant

Phenelzine, sold under the brand name Nardil among others, is a non-selective and irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine family which is primarily used as an antidepressant and anxiolytic to treat depression and anxiety. Along with tranylcypromine and isocarboxazid, phenelzine is one of the few non-selective and irreversible MAOIs still in widespread clinical use.

<span class="mw-page-title-main">Dehydroalanine</span> Chemical compound

Dehydroalanine is a dehydroamino acid. It does not exist in its free form, but it occurs naturally as a residue found in peptides of microbial origin. As an amino acid residue, it is unusual because it has an unsaturated backbone.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Ceftriaxone</span> Antibiotic medication

Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle.

<small>DD</small>-Transpeptidase Bacterial enzyme

DD-Transpeptidase is a bacterial enzyme that catalyzes the transfer of the R-L-αα-D-alanyl moiety of R-L-αα-D-alanyl-D-alanine carbonyl donors to the γ-OH of their active-site serine and from this to a final acceptor. It is involved in bacterial cell wall biosynthesis, namely, the transpeptidation that crosslinks the peptide side chains of peptidoglycan strands.

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<span class="mw-page-title-main">Clavulanic acid</span> Molecule used to overcome antibiotic resistance in bacteria

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<span class="mw-page-title-main">Kanamycin A</span> Antibiotic

Kanamycin A, often referred to simply as kanamycin, is an antibiotic used to treat severe bacterial infections and tuberculosis. It is not a first line treatment. It is used by mouth, injection into a vein, or injection into a muscle. Kanamycin is recommended for short-term use only, usually from 7 to 10 days. Since antibiotics only show activity against bacteria, it is ineffective in viral infections.

<span class="mw-page-title-main">Mitomycins</span> Group of antibiotics

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

<span class="mw-page-title-main">Penicillin-binding proteins</span> Class of proteins

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<span class="mw-page-title-main">D-amino acid oxidase</span> Enzyme

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<span class="mw-page-title-main">D-alanine—D-alanine ligase</span> Enzyme belonging to the ligase family

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References

  1. ↑ Polc P, Pieri L, Bonetti EP, Scherschlicht R, Moehler H, Kettler R, et al. (April 1986). "L-cycloserine: behavioural and biochemical effects after single and repeated administration to mice, rats and cats". Neuropharmacology. 25 (4). Elsevier BV: 411–418. doi:10.1016/0028-3908(86)90236-4. PMID   3012401. S2CID   462885.
  2. 1 2 3 4 5 6 7 "Cycloserine". Drugs.com, The American Society of Health-System Pharmacists. 2024. Retrieved 28 November 2024.
  3. ↑ Gottlieb D, Shaw PD (2012). Mechanism of Action. Springer Science & Business Media. p. 41. ISBN   9783642460517. Archived from the original on 2016-12-20.
  4. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ↑ Nitsche MA, Jaussi W, Liebetanz D, Lang N, Tergau F, Paulus W (August 2004). "Consolidation of human motor cortical neuroplasticity by D-cycloserine" (PDF). Neuropsychopharmacology. 29 (8): 1573–8. doi: 10.1038/sj.npp.1300517 . PMID   15199378.
  6. 1 2 "CYCLOSERINE: Human Health Effects". National Institutes of Health. Archived from the original on 2014-04-16.
  7. ↑ Ori R, Amos T, Bergman H, Soares-Weiser K, Ipser JC, Stein DJ (May 2015). "Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders". The Cochrane Database of Systematic Reviews. 2015 (5): CD007803. doi:10.1002/14651858.CD007803.pub2. PMC   8939046 . PMID   25957940.
  8. 1 2 3 Schade S, Paulus W (April 2016). "D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review". The International Journal of Neuropsychopharmacology. 19 (4): pyv102. doi:10.1093/ijnp/pyv102. PMC   4851259 . PMID   26364274.
  9. ↑ Myers KM, Carlezon WA (June 2012). "D-cycloserine effects on extinction of conditioned responses to drug-related cues". Biological Psychiatry. 71 (11): 947–55. doi:10.1016/j.biopsych.2012.02.030. PMC   4001849 . PMID   22579305.
  10. ↑ Lambert MP, Neuhaus FC (June 1972). "Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W". Journal of Bacteriology. 110 (3): 978–87. doi:10.1128/JB.110.3.978-987.1972. PMC   247518 . PMID   4555420.
  11. 1 2 3 4 5 6 Prosser GA, de Carvalho LP (February 2013). "Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine". The FEBS Journal. 280 (4): 1150–66. doi: 10.1111/febs.12108 . PMID   23286234. S2CID   22305408.
  12. 1 2 Kaushal G, Ramirez R, Alambo D, Taupradist W, Choksi K, Sirbu C (October 2011). "Initial characterization of D-cycloserine for future formulation development for anxiety disorders". Drug Discoveries & Therapeutics. 5 (5): 253–60. doi: 10.5582/ddt.2011.v5.5.253 . PMID   22466372.
  13. ↑ Silverman R (1998). "An Aromatization Mechanism of Inactivation of γ-Aminobutyric Acid Aminotransferase for the Antibiotic l-Cycloserine". Journal of the American Chemical Society. 120 (10): 2256–2267. doi:10.1021/ja972907b.
  14. ↑ Holt GR (6 December 2021). "Principles of plastic surgery of congenital facial abnormalities". Facial Plastic Surgery. 3 (3): 147–154. doi:10.1002/cmdc.202100503. PMC   9293202 . PMID   3459696.
  15. ↑ Uda N, Matoba Y, Kumagai T, Oda K, Noda M, Sugiyama M (June 2013). "Establishment of an in vitro D-cycloserine-synthesizing system by using O-ureido-L-serine synthase and D-cycloserine synthetase found in the biosynthetic pathway". Antimicrobial Agents and Chemotherapy. 57 (6): 2603–2612. doi:10.1128/AAC.02291-12. PMC   3716191 . PMID   23529730.
  16. ↑ Harned RL (21 May 1963). "US3090730A Process for the production of cycloserine". Google Patents.
  17. ↑ Kuehl Jr FA, Wolf FJ, Trenner NR, Peck RL, Buhs RP, Howe E, et al. (1955). "D-4-Amino-3-isoxazolidinone, a new antibiotic". Journal of the American Chemical Society. 77 (8): 2344–5. doi:10.1021/ja01613a105.
  18. ↑ Hidy PH, Hodge EB, Young VV, Harned RL, Brewer GA, Phillips WF, et al. (1955). "Synthesis of D-4-amino-3-isoxazolidinone". Journal of the American Chemical Society. 77 (8): 2346–7. doi:10.1021/ja01613a107.
  19. ↑ Hidy PH, Hodge EB, Young VV, Harned RL, Brewer GA, Phillips WF, et al. (1955). "Structure and reactions of cycloserine". Journal of the American Chemical Society. 77 (8): 2345–6. doi:10.1021/ja01613a106.
  20. ↑ Pollack A (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. Archived from the original on 25 September 2015. Retrieved 21 September 2015.
  21. 1 2 Pollack A (21 September 2015). "Big Price Increase for Tuberculosis Drug Is Rescinded". NYT. Archived from the original on 26 September 2015. Retrieved 24 September 2015.
  22. ↑ Mataix-Cols D, Fernández de la Cruz L, Monzani B, et al. (May 2017). "D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data". JAMA Psychiatry. 74 (5): 501–510. doi:10.1001/jamapsychiatry.2016.3955. hdl: 2066/174490 . PMID   28122091. (Erratum:  doi:10.1001/jamapsychiatry.2017.0144, PMID   28297011 . If the erratum has been checked and does not affect the cited material, please replace {{ erratum |...}} with {{ erratum |...|checked=yes}}.)