A Comprehensive Monograph on L-Cycloserine (Levcycloserine): Pharmacology, Stereochemistry, and Therapeutic Potential

Executive Summary

1.1. Introduction to L-Cycloserine

L-Cycloserine, also known by the International Nonproprietary Name (INN) Levcycloserine, is the (S)-enantiomer of the broad-spectrum antibiotic cycloserine.[1] Identified by the Chemical Abstracts Service (CAS) number 339-72-0 and DrugBank accession ID DB17627, this small molecule represents a case study in pharmacological stereospecificity. It is imperative to distinguish L-Cycloserine from its more widely known (R)-enantiomer, D-Cycloserine (DrugBank ID DB00260), which is marketed under brand names like Seromycin® and is clinically employed as a second-line agent for treating drug-resistant tuberculosis.[3] A significant portion of the publicly available scientific and medical literature conflates the two isomers or uses the term "cycloserine" generically, leading to considerable confusion regarding their distinct pharmacological profiles, mechanisms of action, and therapeutic potential. This report aims to provide a definitive and comprehensive analysis of L-Cycloserine, clarifying its unique properties in contrast to its clinically utilized stereoisomer.

1.2. Core Pharmacological Profile

The defining pharmacological characteristic of L-Cycloserine is its function as a potent and irreversible inhibitor of the enzyme serine palmitoyltransferase (SPT), also known as 3-ketodihydrosphingosine synthetase (EC 2.3.1.50).[2] SPT catalyzes the initial and rate-limiting step in the

de novo biosynthesis of ceramides and all downstream sphingolipids, which are critical components of cell membranes and signaling molecules. The stereospecificity of this action is profound; L-Cycloserine is approximately 100 times more potent in its inhibition of SPT than D-Cycloserine, a distinction that underpins its unique therapeutic and toxicological profile.[2]

1.3. Antimicrobial Activity

Beyond its metabolic effects, L-Cycloserine exhibits significant antimicrobial activity. Notably, it demonstrates superior in vitro potency against Mycobacterium tuberculosis, the causative agent of tuberculosis. Minimum Inhibitory Concentration (MIC) studies have revealed that L-Cycloserine inhibits the growth of M. tuberculosis at a concentration of 0.3 µg/mL, making it approximately 10-fold more potent than the D-isomer (MIC = 2.3 µg/mL).[9] This enhanced activity is attributed to a multi-target mechanism that is distinct from its enantiomer. L-Cycloserine potently inhibits the bacterial branched-chain aminotransferase (MtIlvE), an enzyme essential for amino acid synthesis, and also targets alanine racemase (Alr), an enzyme involved in cell wall precursor synthesis.[2]

1.4. Regulatory and Clinical Status

Despite its potent biological activities, L-Cycloserine is not an approved drug by the U.S. Food and Drug Administration (FDA) or other major regulatory bodies for any clinical indication. It remains an investigational compound used primarily for research purposes.[11] Historically, L-Cycloserine was granted an orphan drug designation by the FDA in 1989 for the treatment of Gaucher's disease, a lysosomal storage disorder related to sphingolipid metabolism. However, this designation did not lead to a marketed product and is now considered lapsed.[13] Consequently, L-Cycloserine is a molecule of considerable scientific interest, possessing a dual profile as a powerful metabolic modulator and a highly potent antibiotic. Its therapeutic potential is significant but is shadowed by substantial, mechanism-based safety concerns that have thus far precluded its clinical development.

Identification and Chemical Properties

2.1. Nomenclature and Identifiers

To eliminate ambiguity and establish a definitive reference, the nomenclature and key identifiers for L-Cycloserine are compiled below. This is particularly crucial given the frequent confusion with its D-enantiomer.

• Generic Name: L-Cycloserine; Levcycloserine (United States Adopted Name and INN).[1]
• IUPAC Name: (4S)-4-amino-1,2-oxazolidin-3-one.[1]
• Synonyms: A comprehensive list of synonyms includes (S)-(-)-Cycloserine, Cyclo-L-serine, L-4-Amino-3-isoxazolidinone, Levcicloserina, Levcycloserinum, L-Oxamicina, (-)-Cycloserine, and (S)-4-Amino-3-isoxazolidinone.[1]
• Key Identifiers:
• DrugBank ID: DB17627 [1]
• CAS Number: 339-72-0 [1]
• ChEBI ID: CHEBI:75592 [1]
• UNII (Unique Ingredient Identifier): AK7DRB7FMO [1]
• PubChem CID: 449215 [18]
• EC Number: 206-427-0 [1]

2.2. Physicochemical Characteristics

The physical and chemical properties of L-Cycloserine are summarized in Table 1. These properties underscore its nature as a small, hydrophilic molecule and provide a basis for understanding its pharmacokinetic behavior.

Table 1: Chemical and Physical Properties of L-Cycloserine

Property	Value	Source(s)
IUPAC Name	(4S)-4-amino-1,2-oxazolidin-3-one	1
CAS Number	339-72-0	1
DrugBank ID	DB17627	1
Molecular Formula	C3​H6​N2​O2​	1
Molecular Weight	102.09 g/mol	1
Appearance	White powder or solid	17
Melting Point	>127 °C (decomposes) to 147 °C. This is notably lower than the D-isomer's melting point of ~155-156 °C.	4
Solubility	Water: Soluble (20-25 mg/mL) DMSO: Soluble (1-8 mg/mL) PBS (pH 7.2): Soluble (10 mg/mL)	2
LogP (XLogP3)	-1.5	1
Optical Rotation	[a]D24​=−108±2∘ (c=1 in H2​O). This levorotatory property confirms the (S)-configuration, in contrast to the dextrorotatory (+) property of the D-isomer.	4
SMILES	C1C@@HN
InChIKey	DYDCUQKUCUHJBH-REOHCLBHSA-N

2.3. Stability and Formulation

L-Cycloserine shares a similar stability profile with its enantiomer. It is unstable in neutral or acidic aqueous solutions, where it can hydrolyze to hydroxylamine and L-serine. The molecule exhibits its greatest stability under basic conditions, with an optimal pH of 11.5. Like the D-isomer, it is hygroscopic and can deteriorate upon absorption of atmospheric water, necessitating storage in a dry environment.

For research purposes, L-Cycloserine is typically stored as a powder at -20°C, where it is stable for several years. Stock solutions in solvents like water or DMSO are generally stable for up to one month when stored at -20°C. For

in vivo studies, it is often formulated in sterile saline for parenteral administration or in co-solvent systems for improved solubility and stability, such as a mixture of 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline.

Pharmacology and Mechanism of Action

3.1. Primary Mechanism: Potent Inhibition of Sphingolipid Biosynthesis

The most distinctive and potent pharmacological action of L-Cycloserine is the irreversible inhibition of serine palmitoyltransferase (SPT), the enzyme that catalyzes the condensation of L-serine and palmitoyl-CoA. This reaction is the committed and rate-limiting step in the

de novo synthesis of all sphingolipids, including ceramides, sphingomyelin, and gangliosides. These lipids are not only structural components of cellular membranes but also critical signaling molecules involved in apoptosis, cell proliferation, and inflammation.

The inhibition of SPT by L-Cycloserine is both highly potent and stereospecific. Multiple independent studies have confirmed that the L-isomer is approximately 100-fold more potent as an inhibitor of SPT than its D-isomer counterpart. For instance, L-Cycloserine can inhibit bacterial SPT activity by 80% at a concentration of 25 µM. This profound difference in potency underscores the stereochemical precision required for interaction with the enzyme's active site. The inhibition is also described as irreversible, suggesting the formation of a stable, likely covalent, adduct with the enzyme or its pyridoxal 5'-phosphate (PLP) cofactor, leading to a prolonged duration of action that outlasts the pharmacokinetic half-life of the drug itself. This potent, on-target activity has been demonstrated across various biological systems, including bacterial SPT, mouse brain microsomes, and rabbit aorta, highlighting its potential as a pharmacological tool for modulating sphingolipid levels in diverse pathological contexts.

3.2. Antimicrobial Mechanisms of Action

3.2.1. Superior Potency Against M. tuberculosis

L-Cycloserine is a significantly more potent antibiotic against M. tuberculosis in in vitro settings compared to the clinically used D-Cycloserine. Studies have established a Minimum Inhibitory Concentration (MIC) for L-Cycloserine of approximately 0.3 µg/mL, which is nearly an order of magnitude lower than the MIC for D-Cycloserine (2.3 µg/mL). This superior potency is not merely an amplification of the same mechanism as its enantiomer but arises from a distinct, multi-target profile.

3.2.2. Multi-Target Inhibition

The enhanced antibacterial effect of L-Cycloserine stems from its ability to inhibit multiple, essential bacterial enzymes simultaneously. This pleiotropic mechanism of action represents a key departure from the D-isomer.

• Branched-Chain Aminotransferase (MtIlvE): A primary and unique target of L-Cycloserine in M. tuberculosis is the branched-chain aminotransferase, MtIlvE. This PLP-dependent enzyme is responsible for the final step in the biosynthesis of the essential branched-chain amino acids L-leucine, L-isoleucine, and L-valine. L-Cycloserine is a time- and concentration-dependent inactivator of MtIlvE and is reported to be a 40-fold better inhibitor of this enzyme than D-Cycloserine. By disrupting this pathway, L-Cycloserine starves the bacterium of crucial building blocks for protein synthesis.
• Alanine Racemase (Alr): L-Cycloserine shares the ability to inhibit alanine racemase with its D-isomer. Alr is a critical enzyme that converts L-alanine to D-alanine, a necessary precursor for peptidoglycan synthesis in the bacterial cell wall. However, the kinetics of enzyme inactivation differ between the two isomers. While the formation of the D-cycloserine-enzyme adduct follows a single exponential process, the interaction with L-Cycloserine occurs in a more complex, two-step process, indicating a distinct stereochemical engagement with the enzyme's active site.
• Lack of D-alanine-D-alanine Ligase (Ddl) Inhibition: A crucial point of differentiation is that L-Cycloserine does not inhibit D-alanine-D-alanine ligase (Ddl). Ddl is the second key enzyme in the D-alanine pathway targeted by D-Cycloserine, responsible for creating the D-Ala-D-Ala dipeptide. The inability of the L-isomer to inhibit Ddl confirms that its antimicrobial mechanism is fundamentally different.

The combination of these effects suggests a powerful, multi-pronged attack on the bacterium. While D-Cycloserine primarily weakens the cell wall by disrupting the D-alanine pathway, L-Cycloserine simultaneously compromises cell wall integrity (via Alr inhibition), cripples essential amino acid synthesis (via MtIlvE inhibition), and potentially disrupts membrane function through its potent inhibition of bacterial sphingolipid synthesis. This multi-target action not only explains its superior in vitro potency but also suggests that it may possess a higher barrier to the development of bacterial resistance compared to inhibitors that act on a single pathway.

3.3. Other Investigated Pharmacological Activities

Beyond its primary roles as an SPT inhibitor and antibiotic, L-Cycloserine has been associated with other biological activities in various research contexts.

• Anti-HIV Activity: Several database entries and commercial supplier descriptions note that L-Cycloserine has been reported to inhibit HIV-1 cytopathic effects, replication, and infectivity. However, the primary literature detailing the mechanism or potency of this activity is not extensively covered in the available materials, and this remains an area of preliminary investigation.
• GABA Transaminase (GABA-T) Inhibition and Anticonvulsant Properties: L-Cycloserine is described as an inhibitor of gamma-aminobutyric acid (GABA) transaminase (GABA-T), the enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. This mechanism, which would lead to increased GABA levels in the brain, is consistent with its reported anticonvulsant properties in preclinical models.
• Clarification on NMDA Receptor Activity: It is critical to address and correct claims found in some sources that attribute N-methyl-D-aspartate (NMDA) receptor agonism to L-Cycloserine. This pharmacological activity is a well-documented and defining characteristic of the D-isomer, D-Cycloserine. D-Cycloserine acts as a partial agonist at the glycine co-agonist site of the NMDA receptor. This action is responsible for both its investigation as a cognitive enhancer in psychiatric disorders and its dose-limiting neurotoxic side effects, such as psychosis and seizures. Rigorous scientific literature does not attribute this mechanism to L-Cycloserine. The absence of NMDA receptor activity is a key differentiator in the toxicological profiles of the two enantiomers.

Pharmacokinetics (ADME)

4.1. General Overview and Data Caveat

The pharmacokinetic (PK) profile of L-Cycloserine in humans has not been formally characterized, as it has never undergone extensive clinical development. The vast majority of available clinical PK data for "cycloserine" pertains to its D-enantiomer (DB00260), which has been used for decades in the treatment of multidrug-resistant tuberculosis (MDR-TB). Given that L- and D-Cycloserine are enantiomers with very similar physicochemical properties (e.g., small size, hydrophilicity), it is reasonable to hypothesize that their absorption, distribution, metabolism, and excretion (ADME) profiles may be comparable. However, this remains an unproven assumption. The following sections summarize the well-documented PK of D-Cycloserine as a proxy, with this important limitation continuously reinforced.

4.2. Absorption

Following oral administration, D-Cycloserine is rapidly and almost completely absorbed from the gastrointestinal tract, with bioavailability reported to be between 70% and 90%. Peak plasma concentrations are typically reached within a few hours of administration. Co-administration with high-fat meals may decrease the rate, but not necessarily the extent, of absorption. Preclinical studies in animal models have confirmed that L-Cycloserine is also orally bioavailable, achieving systemic concentrations sufficient to exert pharmacological effects.

4.3. Distribution

D-Cycloserine is known for its wide distribution throughout the body fluids and tissues. Critically, it readily crosses the blood-brain barrier and achieves significant concentrations in the cerebrospinal fluid (CSF), a property that underlies its prominent neurological side effects. The apparent volume of distribution (

Vd​/F) for D-Cycloserine in adult patients is estimated to be approximately 25 liters, indicating extensive distribution beyond the plasma volume. Similarly, preclinical studies have shown that L-Cycloserine effectively penetrates the central nervous system and distributes to the retina, which is a key prerequisite for its investigation in the treatment of neurological and retinal degenerative diseases.

4.4. Metabolism

D-Cycloserine undergoes minimal hepatic metabolism. It is estimated that approximately 30-35% of an administered dose is metabolized via pathways that are not well characterized, with the majority of the drug remaining unchanged. This low reliance on hepatic metabolism is thought to contribute to its relatively low potential for causing hepatotoxicity, which is a common concern with other anti-tuberculosis agents.

4.5. Excretion

The primary route of elimination for D-Cycloserine is renal excretion. Approximately 60-70% of an orally administered dose is excreted unchanged in the urine via glomerular filtration. As a result, the drug's elimination half-life is highly dependent on renal function and is significantly prolonged in patients with renal impairment. In individuals with normal renal function, the elimination half-life of D-Cycloserine is reported to be in the range of 10 to 12 hours. However, some population PK models have estimated a longer half-life of up to 16.8 hours, which has implications for dosing frequency and time to reach steady-state concentrations.

4.6. Pharmacokinetic Modeling

The pharmacokinetics of D-Cycloserine have been characterized using both one-compartment and two-compartment disposition models in population PK analyses. These models are essential tools for optimizing therapy in MDR-TB, allowing for therapeutic drug monitoring (TDM) and dose adjustments. These studies have consistently identified patient body weight and renal function (e.g., creatinine clearance) as the most significant covariates influencing drug clearance and volume of distribution, highlighting the need for individualized dosing strategies.

Comparative Analysis: L-Cycloserine vs. D-Cycloserine

The distinction between L-Cycloserine and D-Cycloserine is not merely academic; it is fundamental to understanding their pharmacology, therapeutic utility, and safety. These two molecules are not interchangeable mirror images but are functionally distinct entities with different primary targets, potencies, and clinical profiles. D-Cycloserine is an established antibiotic whose clinical use is constrained by off-target neurotoxicity mediated by the NMDA receptor. In stark contrast, L-Cycloserine is a potent metabolic pathway inhibitor whose potential therapeutic applications are limited by the risk of on-target systemic toxicity from its primary mechanism. This dichotomy serves as a textbook example of stereospecificity in drug action, where a subtle change in three-dimensional structure leads to a profound divergence in biological activity. Table 2 provides a systematic, point-by-point comparison to definitively resolve the widespread confusion between these two enantiomers.

Table 2: Comparative Analysis of L-Cycloserine and D-Cycloserine

Sources:

Preclinical Research and Therapeutic Potential

The unique pharmacological profile of L-Cycloserine has positioned it as a compound of interest in several preclinical research areas, distinct from the established applications of its D-isomer.

6.1. Infectious Diseases (Tuberculosis)

Based on its superior in vitro potency and multi-target mechanism against M. tuberculosis, L-Cycloserine presents, on the surface, as a promising candidate for a next-generation anti-TB drug. A drug that is 10-fold more potent than the existing second-line agent (D-Cycloserine) would typically be a high-priority for development, especially in the face of rising drug resistance. However, L-Cycloserine has not advanced into clinical trials for tuberculosis, revealing a significant therapeutic paradox. Its development is likely constrained by the very mechanism that makes it a candidate for other diseases. The potent, irreversible, and systemic inhibition of the fundamental sphingolipid biosynthesis pathway, while contributing to its antimicrobial effect, poses a substantial and likely unacceptable toxicological risk for the months- or years-long treatment regimens required for tuberculosis. The potential for widespread disruption of cellular membrane integrity and signaling across all host tissues creates a safety concern that likely outweighs the benefit of its enhanced potency. Thus, the greatest strength of L-Cycloserine in metabolic modulation becomes its fatal flaw for its application as a systemic antibiotic.

6.2. Lysosomal Storage and Neurodegenerative Diseases

The most explored therapeutic avenue for L-Cycloserine has been as a potential substrate reduction therapy (SRT) for diseases of sphingolipid metabolism.

• Gaucher's & Krabbe Diseases: In lysosomal storage disorders like Gaucher's disease and Krabbe disease, genetic defects lead to the accumulation of specific sphingolipids (glucosylceramide in Gaucher's; galactosylceramide and its toxic derivative psychosine in Krabbe's). The therapeutic rationale for L-Cycloserine is that by inhibiting SPT, the first enzyme in the pathway, it can reduce the overall production of all downstream substrates, thereby decreasing the accumulation of the toxic lipid. This hypothesis was validated in preclinical models of Krabbe disease (the twitcher mouse), where L-Cycloserine administration reduced psychosine levels and modestly extended lifespan.

This rationale led to the FDA granting L-Cycloserine an orphan drug designation for the treatment of Gaucher's disease in 1989. However, this designation never translated into an approved therapy. This failure represents an important lesson in the evolution of drug development. L-Cycloserine acts as a "blunt instrument," inhibiting the entire sphingolipid pathway to target one downstream product. This non-specific approach carries a high risk of disrupting the synthesis of hundreds of other essential sphingolipids throughout the body. The subsequent development and approval of more sophisticated SRTs, such as eliglustat (Cerdelga), which inhibits the more specific downstream enzyme glucosylceramide synthase, demonstrates a critical shift toward greater target specificity to achieve a viable therapeutic window. The history of L-Cycloserine for Gaucher's disease thus serves as a valuable case study in the progression from broad metabolic inhibition to targeted enzyme modulation.

6.3. Retinal Degenerative Diseases

A promising and more recent area of investigation is the use of L-Cycloserine in treating retinal degenerative diseases. Preclinical research in mouse models of light-induced retinal degeneration (LIRD) has shown that systemic administration of L-Cycloserine can significantly protect photoreceptor cells from apoptosis. The proposed mechanism is the inhibition of

de novo ceramide biosynthesis within the retina. Elevated ceramide levels are implicated as a key second messenger in cellular stress and apoptosis. By lowering ceramide production via SPT inhibition, L-Cycloserine appears to reduce oxidative stress and mitochondrial dysfunction in photoreceptor cells. This application is particularly intriguing because it raises the possibility of using localized delivery methods (e.g., intravitreal injection) to achieve a therapeutic effect in the eye while minimizing the systemic exposure and associated toxicological risks of SPT inhibition.

6.4. Metabolic Disorders and Oncology

Emerging preclinical research has explored the utility of L-Cycloserine in other contexts. In obese rat models, inhibiting SPT with L-Cycloserine was shown to reduce ceramide accumulation specifically in slow-twitch skeletal muscle, which in turn halted the progression of insulin resistance. In oncology, studies have demonstrated that inhibiting ceramide biosynthesis with L-Cycloserine can reverse the therapeutic effect of certain cancer drugs, while other studies have shown it can have synergistic effects with chemotherapy agents like capecitabine in colon cancer cell lines by inducing mitochondrial dysfunction. These findings highlight the complex, context-dependent role of ceramide signaling and suggest that L-Cycloserine could be a valuable tool for dissecting these pathways.

Table 3: Summary of Preclinical Investigations and Therapeutic Potential of L-Cycloserine

Therapeutic Area	Proposed Mechanism of Action	Model System(s)	Key Findings	Supporting Source(s)
Tuberculosis	Multi-target inhibition of MtIlvE, Alr, and bacterial SPT.	In vitro M. tuberculosis cultures	~10-fold more potent than D-Cycloserine (MIC 0.3 vs. 2.3 µg/mL).
Krabbe Disease (SRT)	Inhibition of SPT to reduce synthesis of galactosylceramide and toxic psychosine.	Twitcher mouse model	Reduced psychosine levels; modest extension of lifespan.
Gaucher's Disease (SRT)	Inhibition of SPT to reduce synthesis of glucosylceramide.	N/A (Orphan Designation)	Granted orphan drug designation in 1989, but not developed.
Retinal Degeneration	Inhibition of SPT to reduce ceramide-mediated oxidative stress and apoptosis.	Mouse model of LIRD; 661W photoreceptor cells	Protects photoreceptors from cell death; restores neuronal signaling.
Insulin Resistance	Inhibition of SPT to reduce ceramide accumulation in skeletal muscle.	JCR obese rat model	Halted the progression of insulin resistance.
Oncology	Modulation of ceramide biosynthesis and induction of mitochondrial dysfunction.	Colorectal cancer cell lines; xenograft mice	Synergistic effect with capecitabine; reverses effect of SCD1 inhibitors.
HIV Infection	Inhibition of HIV-1 replication and cytopathic effects.	In vitro cell models	Reported anti-HIV activity.

Safety and Toxicology

7.1. GHS Hazard Classification and Handling

As an investigational chemical, L-Cycloserine has a defined hazard profile under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS). It is classified as:

• H302: Harmful if swallowed (Acute Toxicity, Oral, Category 4)
• H332: Harmful if inhaled (Acute Toxicity, Inhalation, Category 4)
• H315: Causes skin irritation (Skin Corrosion/Irritation, Category 2)
• H319: Causes serious eye irritation (Serious Eye Damage/Irritation, Category 2A)
• H335: May cause respiratory irritation (Specific Target Organ Toxicity, Single Exposure, Category 3)

Due to these hazards, standard laboratory handling precautions are required. These include the use of personal protective equipment (PPE) such as protective gloves, safety goggles, and lab coats. Work should be conducted in a well-ventilated area or under a chemical fume hood to avoid inhalation of the powder.

7.2. Clinical and Preclinical Toxicology

The safety profiles of L-Cycloserine and D-Cycloserine are mechanistically distinct and should not be conflated. The failure to separate these profiles can lead to dangerous assumptions about the nature and origin of their respective toxicities.

The well-documented clinical toxicity of "cycloserine" is almost exclusively related to the D-isomer. Its use in tuberculosis is limited by a high incidence of central nervous system (CNS) adverse effects, including drowsiness, confusion, depression, psychosis, and seizures. These effects are a direct consequence of its

off-target activity as a partial agonist at the NMDA receptor in the brain.

In contrast, L-Cycloserine is not known to share this NMDA receptor activity and is therefore not expected to produce the same profile of neuro-psychiatric side effects. The primary toxicological concern for L-Cycloserine stems directly from its potent on-target mechanism: the irreversible, systemic inhibition of SPT. Since sphingolipids are essential for the structure and function of all cells in the body, complete or near-complete inhibition of their synthesis is predicted to be incompatible with life. Even partial inhibition, if sustained, could lead to widespread cellular dysfunction. This on-target toxicity is the central challenge for its therapeutic development. Preclinical studies have raised this concern, noting that its potent inhibitory properties may prevent the identification of a safe and effective therapeutic window for systemic administration.

7.3. Drug Interactions

Formal drug interaction studies have not been conducted for L-Cycloserine. However, the known interactions for the D-isomer provide a cautionary reference. The most significant interaction for D-Cycloserine is with alcohol and other CNS-active agents (e.g., amitriptyline, clozapine, ethionamide), which can potentiate its neurotoxic effects and increase the risk of seizures. Given that L-Cycloserine also penetrates the CNS and has its own distinct mechanisms of action (e.g., GABA-T inhibition), caution would be warranted with co-administration of any CNS-depressant or psychoactive substances until its interaction profile is better understood.

Regulatory Status and Synthesis

8.1. Regulatory Approval Status

L-Cycloserine (Levcycloserine) is not an approved drug in the United States or other major jurisdictions and is available for research use only. This stands in sharp contrast to its enantiomer, D-Cycloserine, which was approved by the FDA in 1964 for the treatment of tuberculosis and certain urinary tract infections and remains a key component of regimens for MDR-TB.

8.2. Orphan Drug Designation for Gaucher's Disease

On August 1, 1989, the FDA granted L-Cycloserine an orphan drug designation for the "Treatment of Gaucher's disease". The sponsor for this designation was Dr. Meir M. Lev at The City College of the City University of New York. This designation was based on the rationale that inhibiting SPT could serve as a form of substrate reduction therapy for the disease. However, the designation status is now listed as "Designated" but "Not FDA Approved for Orphan Indication," indicating that the compound did not successfully navigate the clinical trial process to gain marketing approval for this use. As discussed previously, this outcome likely reflects the challenges posed by the non-specific, systemic nature of its SPT inhibition, a hurdle that was later overcome by more targeted SRT agents.

8.3. History and Synthesis

The compound now known as cycloserine was first isolated nearly simultaneously in the mid-1950s by two independent research teams. Workers at Merck & Co. isolated a compound they named oxamycin from a species of Streptomyces, while a team at Eli Lilly isolated the same molecule from strains of Streptomyces orchidaceus. These natural sources produce the D-enantiomer. L-Cycloserine was later identified as a natural product isolated from the bacterium

Erwinia uredovora.

The chemical synthesis of cycloserine has evolved significantly over time. The first reported synthesis by the Stammer group in 1955 produced a racemic mixture of the D- and L-isomers. Enantioselective synthesis was achieved shortly after, with a 1957 report describing the synthesis of the pure D-enantiomer. In recent decades, chemical synthesis was revolutionized by the development of more efficient approaches that utilize the inexpensive and readily available chiral precursor D-serine (the enantiomer of the common amino acid L-serine) to produce D-Cycloserine enantioselectively. Similar strategies can be employed starting from L-serine to produce L-Cycloserine.

Conclusion

L-Cycloserine (Levcycloserine, DB17627) is a pharmacologically distinct molecule from its clinically utilized enantiomer, D-Cycloserine. While the latter is an established second-line antibiotic for tuberculosis, L-Cycloserine is an investigational compound defined by a different set of primary targets and a unique therapeutic and toxicological profile.

The defining characteristic of L-Cycloserine is its action as a potent, irreversible inhibitor of serine palmitoyltransferase (SPT), the gatekeeper enzyme of sphingolipid biosynthesis. This activity is approximately 100-fold more potent than that of the D-isomer and positions L-Cycloserine as a powerful tool for modulating cellular metabolism. This mechanism forms the basis for its promising preclinical activity in substrate reduction therapy for lysosomal storage diseases, in protecting against retinal degeneration, and in emerging research in metabolic disorders and oncology.

Concurrently, L-Cycloserine is a markedly more potent antibiotic against M. tuberculosis in vitro, exhibiting a multi-target mechanism that includes the unique inhibition of the essential enzyme MtIlvE. This pleiotropic action suggests a potential for greater efficacy and a higher barrier to resistance than existing therapies.

However, the therapeutic potential of L-Cycloserine is shadowed by a significant safety paradox. Its potent, systemic inhibition of the vital sphingolipid pathway, while therapeutically relevant, carries a high intrinsic risk of on-target toxicity. This concern has likely precluded its development as a systemic antibiotic for tuberculosis and led to the failure of its early exploration as a substrate reduction therapy for Gaucher's disease. The future clinical development of L-Cycloserine, or derivatives thereof, will likely depend on overcoming this central challenge. The development of tissue-specific delivery systems—such as localized administration for retinal diseases—or the design of next-generation analogues with improved therapeutic indices may be necessary to unlock the considerable potential of this potent and scientifically fascinating molecule.

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