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]

Quick Facts Clinical data, Trade names ...

Cycloserine

Clinical data
Trade names	Seromycin
Other names	D-cycloserine, 4-amino-3-isoxazolidinone
AHFS/Drugs.com	Monograph
License data	US DailyMed: Seromycin
ATC code	J04AB01 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	~70% to 90%
Metabolism	Liver
Elimination half-life	10 hrs (normal kidney function)
Excretion	Kidney
Identifiers
IUPAC name (R)-4-Amino-1,2-oxazolidin-3-one
CAS Number	68-41-7 Y
PubChem CID	6234
DrugBank	DB00260 Y
ChemSpider	5998 Y
UNII	95IK5KI84Z
KEGG	D00877 Y
ChEBI	CHEBI:40009 Y
ChEMBL	ChEMBL771 Y
NIAID ChemDB	007654
CompTox Dashboard (EPA)	DTXSID8022870
ECHA InfoCard	100.000.626
Chemical and physical data
Formula	C3H6N2O2
Molar mass	102.093 g·mol−1
3D model (JSmol)	Interactive image
Melting point	155 to 156 °C (311 to 313 °F) (dec.)
SMILES O=C1NOC[C@H]1N
InChI InChI=1S/C3H6N2O2/c4-2-1-7-5-3(2)6/h2H,1,4H2,(H,5,6)/t2-/m1/s1 Y Key:DYDCUQKUCUHJBH-UWTATZPHSA-N Y
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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]

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, very unclear and still being explored.^[8]

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]

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]}

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]

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]

Some experimental evidence suggests that D-cycloserine aids in learning by helping form stronger neural connections.^[22] It has been investigated as an aid to facilitate exposure therapy in people with PTSD and anxiety disorders,^[23][24][25] and treatment with schizophrenia.^[26] In a clinical trial, a course of D-cycloserine combined with a single dose of ketamine was investigated for treatment resistant bipolar depression. When administered for 8 weeks after a ketamine infusion, cycloserine appeared to potentiate the antidepressant effects in all trial participants.^[27] However, a 2019 clinical trial showed no statistically significant difference between the D-cycloserine and placebo groups when it came to maintaining the antidepressant effect of a single ketamine infusion. The authors suggest several possible explanations for this nonsignificance, namely the inclusion of high-risk or severely treatment-resistant participants as well as a possible confounding carryover effect from the ketamine infusion phase. Although the results point to D-cycloserine having a stronger antisuicidal effect than placebo, the authors caution that this difference might be attributed to the placebo group feeling worse than the D-cycloserine feeling better.^[28] A combination drug, cycloserine/lurasidone, containing D-cycloserine and the atypical antipsychotic lurasidone is being developed for acute suicidal ideation/behavior.^[29]