Cycloserine, sold under the brand name Seromycin, is a

GABA transaminase inhibitor In pharmacology, a GABA transaminase inhibitor is an enzyme inhibitor that acts upon GABA transaminase. Inhibition of GABA transaminase enzymes reduces the degradation of GABA, leading to increased neuronal GABA concentrations. Examples include va ...

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 bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

, used to treat

tuberculosis Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, ...

. Specifically it is used, along with other

antituberculosis medication Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB). The medical standard for active TB is a short course treatment involving a combination of isoniazid, rifampicin (also known as Rifampin), py ...

s, for active

drug resistant tuberculosis Tuberculosis management describes the techniques and procedures utilized for treating tuberculosis (TB). The medical standard for active TB is a short course treatment involving a combination of isoniazid, rifampicin (also known as Rifampin), py ...

. It is given by mouth. Common side effects include

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

, 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 stimuli. In everyday speech this is generally referred to as num ...

. It is not recommended in people who have

kidney failure Kidney failure, also known as end-stage kidney disease, 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 failure is classified as eit ...

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

, depression, or are

alcoholics Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomina ...

. It is unclear if use during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

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

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...

. Cycloserine was discovered in 1954 from a type of ''

Streptomyces ''Streptomyces'' is the largest genus of Actinomycetota and the type genus of the family Streptomycetaceae. Over 500 species of ''Streptomyces'' bacteria have been described. As with the other Actinomycetota, streptomycetes are gram-positiv ...

''. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

Medical uses

Tuberculosis

For the treatment of tuberculosis, cycloserine is classified as a second-line drug, i.e. 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 where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...

, confusion,

paresthesias Paresthesia is an abnormal sensation of the skin (tingling, pricking, chilling, burning, numbness) with no apparent physical cause. Paresthesia may be transient or chronic, and may have any of dozens of possible underlying causes. Paresthesias ar ...

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. In other words, it is a condition in which problems effective ...

, hyperirritability,

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavi ...

convulsions 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 sometimes used as a ...

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

paresis In medicine, paresis () is a condition typified by a weakness of voluntary movement, or by partial loss of voluntary movement or by impaired movement. When used without qualifiers, it usually refers to the limbs, but it can also be used to desc ...

, and

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

, while alcohol consumption may increase the risk of seizures. Coadministration of

pyridoxine Pyridoxine, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disor ...

can reduce the incidence of some of these CNS side effects (e.g. convulsions) caused by cycloserine.

Psychiatry

A 2015

Cochrane review Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...

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.

Mechanism of action

Cycloserine works as an antibiotic by inhibiting cell-wall

biosynthesis Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecul ...

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

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrio ...

stages of

peptidoglycan Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like peptidoglycan layer outside the plasma membrane, the rigid cell wall (murein sacculus) characteristic of most ba ...

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

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

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 together. 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 ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

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

Chemical properties

Under mildly acidic conditions, cycloserine hydrolyzes to give

hydroxylamine Hydroxylamine is an inorganic compound with the formula . The material is a white crystalline, hygroscopic compound.Greenwood and Earnshaw. ''Chemistry of the Elements.'' 2nd Edition. Reed Educational and Professional Publishing Ltd. pp. 431–43 ...

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 Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form ...

) 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.'' sucessfully 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 an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and ...

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

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

There is some experimental evidence to suggest that D-cycloserine aids in learning by helping form stronger neural connections. It has been investigated as an aid to facilitate

exposure therapy Exposure therapy is a technique in behavior therapy to treat anxiety disorders. Exposure therapy involves exposing the target patient to the anxiety source or its context without the intention to cause any danger (desensitization). Doing so is thou ...

in people with

PTSD Post-traumatic stress disorder (PTSD) is a mental and behavioral disorder that can develop because of exposure to a traumatic event, such as sexual assault, warfare, traffic collisions, child abuse, domestic violence, or other threats on ...

and anxiety disorders as well as treatment with schizophrenia. 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.

References

External links

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