Chemistry:Cycloserine

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Cycloserine, sold under the brand name Seromycin, is a broad-spectrum antibiotic used as a second-line treatment for advanced tuberculosis and, rarely, urinary tract infections (UTIs).[1] Specifically, it is used in conjunction with other antituberculosis medications for the treatment of active drug resistant tuberculosis.[1] Cycloserine's use for the treatment of UTIs is similarly alternative, with the drug being primarily reserved for when conventional therapies have failed and antimicrobial susceptibility is demonstrated.[1] It is administered orally.[1]

Cycloserine is a structural analogue of the amino acid D-alanine and works by inhibiting bacterial cell wall synthesis.[1] As cycloserine is able to penetrate the central nervous system, it may cause side effects including headaches, drowsiness, depression, dizziness, vertigo, confusion, paresthesias, dysarthria, hyperirritability, psychosis, convulsions, and shaking (tremors).[2][3] Overdose of cycloserine may result in paresis, seizures, and coma, while alcohol consumption may increase the risk of seizures.[3] Coadministration of pyridoxine, or vitamin B6, may reduce the incidence of some CNS-related side effects.[4] Cycloserine is not recommended for those with kidney failure, epilepsy, depression, or alcoholism.[1] While animal studies have shown adverse effects, it is unknown if cycloserine use during pregnancy poses a developmental risk to human fetuses.[1][5]

Derived simultaneously by Eli Lilly and Merck from Streptomyces in 1954,[6] Cycloserine was widely used in the 1950s and 1960s as a primary treatment for acute UTIs and tuberculosis. Upon the discovery of its neuropsychiatric side effects, usage decreased dramatically beginning in the 1970s.[7] Cycloserine is classified as a Group B agent for the treatment of multidrug-resistant tuberculosis by the World Health Organization, a classification that defines it as a "conditionally recommended [agent] of second choice."[8] Additionally, it is on the World Health Organization's List of Essential Medicines.[9] Cycloserine has received some research interest from the field of psychiatry, most notably in the formulation of cycloserine/lurasidone as a treatment for bipolar depression and suicidal ideation.[7]

Medical uses

Tuberculosis

Cycloserine is used primarily for the treatment of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains of M. tuberculosis, remaining a second- or third-line of treatment for the condition due to its significant neurological and psychological side effects. Cycloserine is always used as part of a multidrug regimen. Because the drug leaves users susceptible to high blood concentrations and systemic toxicity, users require frequent renal, hepatic and hematologic laboratory monitoring.[1]

Urinary tract infections

Cycloserine has demonstrated clinical efficacy against multi-drug resistant urinary pathogens, being approved for the treatment of acute UTIs caused by E. coli and Enterobacter species.[1] Additionally, cycloserine has shown in vitro activity against drug-resistant strains of Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii.[7] Cycloserine's use in treating UTIs is extremely uncommon both due to its comparatively lower efficacy against traditional antibiotics, as well as its significant neurological and psychological side effects.[1] Consequently, it is treated as a drug of last resort, used when other primary options have been exhausted.

Pharmacology

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.[12]

L-Cycloserine is known to act as a GABA transaminase inhibitor (GABA-T inhibitor) and to have anticonvulsant effects.[13][14]

Chemistry

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine.[15][16] Cycloserine can be conceptualized as a cyclized version of serine, with an oxidative loss of dihydrogen to form the nitrogen-oxygen bond. Cycloserine is stable under basic conditions, with the greatest stability at pH = 11.5.[15]

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.[17]

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.[18]

A 1963 patent describes industrial production of the drug by bacterial fermentation.[19] It is unclear what process is used in the 21st century, fermentation, or chemical synthesis.

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.[20] The same team prepared the molecule synthetically.[21] Workers at Eli Lilly isolated the compound from strains of Streptomyces orchidaceus. It was shown to hydrolyze to serine and hydroxylamine.[22]

Society and culture

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.[23]

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.[24]

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.[24]

Research

Psychiatric disorders

A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015.[25] Another review found preliminary evidence of benefit.[12] Evidence for use in addiction is tentative but also unclear.[26]

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,[27] and had potential for use as a therapy in psychiatric diseases.[12] Adding D-cycloserine to exposure therapy did not improve results over exposure therapy alone in a 2025 meta-analysis of children and teenagers with OCD.[28]

Recent research has investigated the use of cycloserine for augmentation of transcranial magnetic stimulation in the treatment of depression, based on its putative effects as a neuroplastogen.[29] Preliminary studies have found adding cycloserine improves response and remission rates compared to rTMS alone.[30][31]

Possible hallucinogenic effects

Cycloserine is closely structurally related to muscimol, a GABAA receptor agonist and hallucinogen found in Amanita muscaria.[32] It has been said to produce effects in humans, including mental confusion, acute psychosis, convulsions, and other abnormal behavioral states, which are reminiscent of those of muscimol.[32]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Cycloserine". Drugs.com, The American Society of Health-System Pharmacists. 2024. https://www.drugs.com/monograph/cycloserine.html. 
  2. ↑ "Consolidation of human motor cortical neuroplasticity by D-cycloserine". Neuropsychopharmacology 29 (8): 1573–1578. August 2004. doi:10.1038/sj.npp.1300517. PMID 15199378. 
  3. ↑ 3.0 3.1 "CYCLOSERINE: Human Health Effects". National Institutes of Health. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+68-41-7. 
  4. ↑ "Vitamin B6 Fact Sheet for Health Professionals". National Institutes of Health. https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/. 
  5. ↑ "Cycloserine Pregnancy and Breastfeeding Warnings". https://www.drugs.com/pregnancy/cycloserine.html. 
  6. ↑ Mechanism of Action. Springer Science & Business Media. 2012. p. 41. ISBN 978-3-642-46051-7. https://books.google.com/books?id=xjPtCAAAQBAJ&pg=PA41. 
  7. ↑ 7.0 7.1 7.2 "NRX-101 (D-Cycloserine + Lurasidone) Is Active against Drug-Resistant Urinary Pathogens In Vitro". Antibiotics (National Institutes of Health) 13 (4): 308. March 2024. doi:10.3390/antibiotics13040308. PMID 38666984. 
  8. ↑ "WHO consolidated guidelines on drug-resistant tuberculosis treatment". World Health Organization. https://iris.who.int/server/api/core/bitstreams/30d89c8e-8e59-4f52-82b4-9a30882a09bf/content. 
  9. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  10. ↑ "Mechanism of D-cycloserine action: alanine racemase from Escherichia coli W". Journal of Bacteriology 110 (3): 978–987. June 1972. doi:10.1128/JB.110.3.978-987.1972. PMID 4555420. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 "Kinetic mechanism and inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by the antibiotic D-cycloserine". The FEBS Journal 280 (4): 1150–1166. February 2013. doi:10.1111/febs.12108. PMID 23286234. 
  12. ↑ 12.0 12.1 12.2 "D-Cycloserine in Neuropsychiatric Diseases: A Systematic Review". The International Journal of Neuropsychopharmacology 19 (4). April 2016. doi:10.1093/ijnp/pyv102. PMID 26364274. 
  13. ↑ "L-cycloserine: behavioural and biochemical effects after single and repeated administration to mice, rats and cats". Neuropharmacology (Elsevier BV) 25 (4): 411–418. April 1986. doi:10.1016/0028-3908(86)90236-4. PMID 3012401. 
  14. ↑ "Effect of L-cycloserine on brain GABA metabolism". Canadian Journal of Physiology and Pharmacology 56 (1): 62–68. February 1978. doi:10.1139/y78-009. PMID 638858. 
  15. ↑ 15.0 15.1 "Initial characterization of D-cycloserine for future formulation development for anxiety disorders". Drug Discoveries & Therapeutics 5 (5): 253–260. October 2011. doi:10.5582/ddt.2011.v5.5.253. PMID 22466372. 
  16. ↑ "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. 1998. doi:10.1021/ja972907b. Bibcode: 1998JAChS.120.2256O. 
  17. ↑ "Principles of Plastic Surgery of Congenital Facial Abnormalities". Facial Plastic Surgery 3 (03): 147–154. 1986. doi:10.1055/s-2008-1064836. PMID 3459696. 
  18. ↑ "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. June 2013. doi:10.1128/AAC.02291-12. PMID 23529730. 
  19. ↑ "US3090730A Process for the production of cycloserine". 21 May 1963. https://patents.google.com/patent/US3090730A/en. 
  20. ↑ "D-4-Amino-3-isoxazolidinone, a new antibiotic". Journal of the American Chemical Society 77 (8): 2344–2345. 1955. doi:10.1021/ja01613a105. Bibcode: 1955JAChS..77.2344K. 
  21. ↑ "Synthesis of D-4-amino-3-isoxazolidinone". Journal of the American Chemical Society 77 (8): 2346–2347. 1955. doi:10.1021/ja01613a107. Bibcode: 1955JAChS..77.2346S. 
  22. ↑ "Structure and reactions of cycloserine". Journal of the American Chemical Society 77 (8): 2345–2346. 1955. doi:10.1021/ja01613a106. Bibcode: 1955JAChS..77.2345H. 
  23. ↑ "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. 20 September 2015. https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html?ref=health&_r=0. 
  24. ↑ 24.0 24.1 "Big Price Increase for Tuberculosis Drug Is Rescinded". NYT. 21 September 2015. https://www.nytimes.com/2015/09/22/business/big-price-increase-for-tb-drug-is-rescinded.html?_r=0. 
  25. ↑ "Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders". The Cochrane Database of Systematic Reviews 2015 (5). May 2015. doi:10.1002/14651858.CD007803.pub2. PMID 25957940. 
  26. ↑ "D-cycloserine effects on extinction of conditioned responses to drug-related cues". Biological Psychiatry 71 (11): 947–955. June 2012. doi:10.1016/j.biopsych.2012.02.030. PMID 22579305. 
  27. ↑ "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. May 2017. doi:10.1001/jamapsychiatry.2016.3955. PMID 28122091.  (Erratum: doi:10.1001/jamapsychiatry.2017.0144, PMID 28297011)
  28. ↑ "Treatment of Obsessive-Compulsive Disorder in Children and Youth: A Meta-Analysis". Pediatrics 155 (3). December 2024. doi:10.1542/peds.2024-068992. PMID 39639456. 
  29. ↑ "Serum levels of D-cycloserine predict antidepressant effects in pharmacologically enhanced intermittent theta-burst stimulation". Journal of Affective Disorders 377: 60–67. May 2025. doi:10.1016/j.jad.2025.02.062. PMID 39986577. 
  30. ↑ "Real-World Effectiveness of a Single-Day Regimen for Transcranial Magnetic Stimulation Using Optimized, Neuroplastogen-Enhanced Techniques in Anxiety (ONE-A).". Transcranial Magnetic Stimulation 3: 100123. April 2025. 
  31. ↑ "Efficacy of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation for Major Depressive Disorder: A Randomized Clinical Trial". JAMA Psychiatry 79 (12): 1153–1161. December 2022. doi:10.1001/jamapsychiatry.2022.3255. PMID 36223114. 
  32. ↑ 32.0 32.1 "Miscellaneous Hallucinogens". Hallucinogenic Agents. Bristol: Wright-Scientechnica. 1975. pp. 196–216. ISBN 978-0-85608-011-1. OCLC 2176880. https://bitnest.netfirms.com/external/Books/978-0-85608-011-1. "However, the closely related antibiotic oxamycin [(d-cycloserine)] (7.6) produces mental confusion, acute psychotic episodes, convulsions, and other abnormal behavioural states in man reminiscent of the isoxazoles [like muscimol and ibotenic acid] contained in Amanita muscaria (Farnsworth, 1968)." 

Further reading

  • Hagers Handbuch der pharmazeutischen Praxis: Folgeband 4: Stoffe A–K.. Birkhäuser. 1999. ISBN 978-3-540-52688-9. 



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