Cycloserine, sold under the brand name Seromycin, is a GABA transaminase inhibitor and an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

, used to treat

tuberculosis Tuberculosis (TB), also known colloquially as the "white death", or historically as consumption, is a contagious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can al ...

. Specifically it is used, along with other antituberculosis medications, for active drug resistant tuberculosis. It is given by mouth. Common side effects include allergic reactions,

seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

, sleepiness, unsteadiness, and

numbness Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to Sensory receptor, sensory stimuli. In everyday speech this is generally r ...

. It is not recommended in people who have

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

, depression, or are alcoholics. It is unclear if use during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

is safe for the baby. Cycloserine is similar in structure to the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

D-alanine and works by interfering with the formation of the bacteria's

cell wall A cell wall is a structural layer that surrounds some Cell type, cell types, found immediately outside the cell membrane. It can be tough, flexible, and sometimes rigid. Primarily, it provides the cell with structural support, shape, protection, ...

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

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 Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...

, confusion, paresthesias,

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. It is a condition in which problems effectively occur with the ...

, hyperirritability,

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

, convulsions, and shaking (tremors). Overdose of cycloserine may result in

paresis In medicine, paresis (), compound word from Greek , (πᾰρᾰ- “beside” + ἵημι “let go, release”), is a condition typified by a weakness of voluntary movement, or by partial loss of voluntary movement or by impaired movement. Whe ...

, and

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...

, while

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

consumption may increase the risk of seizures. Coadministration of pyridoxine can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.

Pharmacology

Mechanism of action

Cycloserine works as an antibiotic by inhibiting cell-wall

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

in bacteria. As a cyclic analogue of D-alanine, cycloserine acts against two crucial enzymes important in the cytosolic stages of

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating ...

synthesis: alanine racemase (Alr) and D-alanine:D-alanine ligase (Ddl). The first

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

is a pyridoxal 5'-phosphate-dependent enzyme which converts the L-alanine to the D-alanine form. 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. If both of these enzymes are inhibited, then D-alanine residues cannot form and previously formed D-alanine molecules cannot be joined. This effectively leads to inhibition of peptidoglycan synthesis. Psychiatric use is suggested based on partial

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

agonism, which improves neural plasticity in lab animals. The degree of clinical usefulness is, as aforementioned, unclear and still being explored, as of 2016.

Chemistry

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give hydroxylamine and D-serine. 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.

Synthesis

Initial approaches to synthesize the compound was first published in 1955, when the Stammer group produced a racemic synthesis from ‐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 -serine (mirror form of normal L-serine) were published by different groups. The biosynthesis of the compound is defined by a ten-gene cluster. -serine and -arginine are converted to O-ureido--serine, flipped to O-ureido--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. A 1963 patent describes industrial production of the drug by bacterial fermentation. 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''. The same team prepared the molecule synthetically. Workers at

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was a Union Army officer, pharmacist, chemist, and businessman who founded Eli Lilly and Company. Lilly enlisted in the Union Army during the American Civil War and recruited a company of men to ...

isolated the compound from strains of ''Streptomyces orchidaceus''. It was shown to hydrolyze to serine and hydroxylamine.

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. 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".

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. In 2015, the cost in the United States was increased to a month and then decreased to per month.

Research

Psychiatric disorders

A 2015 Cochrane review found no evidence of benefit in anxiety disorders as of 2015. Another review found preliminary evidence of benefit. Evidence for use in addiction is tentative but also unclear. Reviews in 2016-17 found that cycloserine produced a small improvement in

cognitive behavioral therapy Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and chang ...

for

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, obsessive-compulsive disorder, and

post-traumatic stress disorder Post-traumatic stress disorder (PTSD) is a mental disorder that develops from experiencing a Psychological trauma, traumatic event, such as sexual assault, domestic violence, child abuse, warfare and its associated traumas, natural disaster ...

, and had potential for use as a therapy in psychiatric diseases.

Possible hallucinogenic effects

Cycloserine is closely structurally related to muscimol, a GABA_A receptor

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

and

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

found in ''

Amanita muscaria ''Amanita muscaria'', commonly known as the fly agaric or fly amanita, is a basidiomycete fungus of the genus ''Amanita''. It is a large white-lamella (mycology), gilled, white-spotted mushroom typically featuring a bright red cap covered with ...

''. It has been said to produce effects in humans, including mental confusion, acute psychosis,

convulsion A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

s, and other abnormal behavioral states, which are reminiscent of those of muscimol.