What is the mechanism of action (Moa) of Ethambutol (Ethambutol hydrochloride)?

From the Guidelines

Ethambutol's mechanism of action involves inhibiting arabinosyl transferases, which contribute to M. tuberculosis cell wall synthesis. This is based on the most recent and highest quality study available, which was published in 2019 in the American Journal of Respiratory and Critical Care Medicine 1. The drug works by inhibiting the synthesis of the mycobacterial cell wall, specifically by blocking the action of arabinosyl transferases, enzymes that are essential for the formation of the cell wall component arabinogalactan. Some key points about ethambutol include:

• It is used in standard regimens for treatment of drug-susceptible TB and commonly used in regimens for MDR-TB 1
• The effectiveness of ethambutol is directly related to dose, with a dose of 25 mg/kg being more effective than a dose of 15 mg/kg 1
• The use of ethambutol as part of the first-line drug-susceptible TB regimen rests largely on its ability to prevent the emergence of resistance, which is a substantial concern among patients with MDR-TB 1
• Ethambutol is associated with increased success when used to treat patients whose isolates are susceptible to the drug 1

From the FDA Drug Label

ETHAMBUTOL HCl diffuses into actively growing Mycobacterium cells such as tubercle bacilli ETHAMBUTOL HCl appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. The Mechanism of Action (MoA) of ethambutol is the inhibition of the synthesis of one or more metabolites in Mycobacterium cells, leading to impairment of cell metabolism, arrest of multiplication, and cell death 2.

• The drug diffuses into actively growing Mycobacterium cells.
• It inhibits the synthesis of one or more metabolites.
• This leads to impairment of cell metabolism, arrest of multiplication, and cell death.

From the Research

Mechanism of Action of Ethambutol

The mechanism of action of ethambutol involves the inhibition of cell wall synthesis in Mycobacterium tuberculosis. Key points include:

• Ethambutol targets the biosynthesis of the cell wall, inhibiting the synthesis of both arabinogalactan and lipoarabinomannan (LAM) 3
• It acts via inhibition of three arabinosyltransferases: EmbA, EmbB, and EmbC, which are required for the synthesis of arabinogalactan and LAM 3, 4
• EmbC is essential for the viability of M. tuberculosis and is involved in the synthesis of LAM, and mutations in EmbC that reduce its arabinosyltransferase activity result in increased sensitivity to ethambutol 3
• Ethambutol selectively blocks apical cell wall synthesis, but not cell division, explaining its bacteriostatic effect 5
• The drug inhibits the synthesis of the arabinan component of the mycobacterial cell wall core polymer, arabinogalactan, and also inhibits biosynthesis of the arabinan of lipoarabinomannan 6

Effects on Cell Wall Synthesis

The effects of ethambutol on cell wall synthesis include:

• Inhibition of galactan synthesis in the cell wall core 6
• Cleavage of arabinosyl residues present in the mycobacterial cell wall, resulting in the removal of more than 50% of the arabinan in the cell wall core 6
• Disruption of the mycobacterial cell wall, providing a molecular explanation for the known synergetic effects of ethambutol with other chemotherapeutic agents 6

Structural Basis of Inhibition

The structural basis of ethambutol inhibition involves:

• Binding of ethambutol to the same site as both substrates in EmbB and EmbC, inhibiting arabinosyltransferases 4
• Location of most drug-resistant mutations near the ethambutol binding site 4