Cycloserine

Chemical and physical properties

Cycloserine (or D-cycloserine) is a structurally simple molecule provided of broad spectrum antibiotic activity (then active on Gram positive and Gram negative bacteria).  Chemically speaking is a cyclic hydroxamate . Being a small and hydrophilic molecule is perfectly capable to go through the porins. It gets into bacteria cytoplasm (where it actually performs is action) through passive diffusion or transport by organic anions carrier.

It is a zwitterionic molecule; this one further account for the great membrane penetration ability (it is polar and hydrophilic but electrically neutral at the same time):

Isolated from Streptomyces garyphalus but nowadays totally produced via organic synthesis.

Pharmacokinetic properties

Shows good absorption after oral subministration (OS) and good tissue distribution. Overcomes the BBB.

Half-life: 12h

Elimination: urinary predominantly

Activity and toxicity

Broad spectrum. Active also on Mycobacteriunm Tubercolosis. Nowadays considered a second choice drug because of its relevant side effects dealing above all with the central nervous system (see pharmacokinetic). This specific kind of toxicity is due to the structure similarity (look at the picture below) with the neurotransmitters glycine and L-aspartate (D-cycloserine interacts with their receptors).

Mechanism of action 

D-cycloserine interferes with a specific step in the biosynthesis of the bacterial cell wall (peptidoglycan).

It is actually a dual mechanism of action and the resulting effect is BACTERICIDE. Indeed this molecule inibits two different enzymes: the L-ala racemase (or alanine racemase) and the D-ala D-ala ligase, preventing the formation of the D-ala D-ala dimer (essential considering it allows the formation of crossed bonds in the bacterial cell wall ). Turns out a weakened cell wall that is no more able to stand the osmotic pressure, and then collapse (osmotic lysis).

The inibition of L-ala Racemase is non-competitive (via secondary bonds).

The D-ala D-ala ligase suffers instead a competitive inibition (covalent bonding of cycloserine with the coenzyme pyridoxal phosphate).

Synthesis

For a detailed explanation of the synthetic process: Cycloserine synthesis

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