Description

Cycloserine is a broad-spectrum antibiotic that is a structural analog of the amino acid D-alanine. It is a second-line antitubercular agent used primarily for the treatment of drug-resistant strains of Mycobacterium tuberculosis. Due to its potential for serious central nervous system (CNS) side effects, its use is typically reserved for cases where first-line drugs are either ineffective or not tolerated.

Indications

Cycloserine is a crucial component of multi-drug regimens for the treatment of tuberculosis. Its main indications are:

• Multidrug-resistant tuberculosis (MDR-TB): It is used in combination with other antituberculosis agents to treat strains of M. tuberculosis that are resistant to at least isoniazid and rifampicin, the two most potent first-line drugs.

• Extensively drug-resistant tuberculosis (XDR-TB): It is also part of treatment regimens for this more severe form of tuberculosis.

• Urinary tract infections (UTIs): In some cases, it can be used to treat UTIs caused by susceptible bacteria.

Mechanism of Action

The antibiotic effect of cycloserine is due to its interference with bacterial cell wall synthesis. Its mechanism is unique because it targets two key enzymes in the early stages of peptidoglycan formation, which is a critical component of the bacterial cell wall.

1. D-Alanine Analog: Cycloserine has a structure very similar to that of D-alanine. This structural similarity allows it to act as a competitive inhibitor of two crucial enzymes.

2. Inhibition of Alanine Racemase: The first enzyme it targets is alanine racemase. This enzyme is responsible for converting L-alanine (a common amino acid) into D-alanine, which is a necessary building block for the bacterial cell wall. By inhibiting this enzyme, cycloserine prevents the formation of D-alanine.

3. Inhibition of D-Alanine Ligase: The second enzyme it targets is D-alanine:D-alanine ligase. This enzyme joins two molecules of D-alanine together to form a D-alanyl-D-alanine dipeptide, which is a key component of the peptidoglycan layer. By inhibiting this enzyme, cycloserine prevents this critical bond from forming.

The dual inhibitory action of cycloserine on two sequential steps in cell wall synthesis makes it a particularly effective antibiotic. By preventing the bacteria from building a functional cell wall, it compromises the structural integrity of the bacterium, leading to its death.

A notable side effect of cycloserine is its ability to cross the blood-brain barrier and act as a partial agonist at the glycine site of the NMDA receptor, which can lead to neuropsychiatric side effects such as anxiety, depression, psychosis, and seizures.