Ethambutol is an antibiotic primarily used in combination with other medications to treat tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis. It is a bacteriostatic drug, meaning it works by stopping the bacteria from multiplying, rather than killing them directly. This action helps to control the infection and is often part of a multi-drug regimen to prevent the development of drug resistance.
The Unique Target: The Mycobacterial Cell Wall
The Mycobacterium tuberculosis bacterium possesses a cell wall that is complex and robust, setting it apart from many other types of bacteria. This elaborate structure is important for the bacterium’s survival, virulence, and resistance to various environmental stresses and antibiotics.
A significant component of this cell wall is the mycolyl-arabinogalactan-peptidoglycan (mAGP) complex. The arabinogalactan layer, a highly branched polysaccharide, acts like the “rebar” in reinforced concrete, providing structural integrity. It links the inner peptidoglycan layer to the outermost mycolic acid layer.
The cell wall’s intricate structure, particularly its waxy mycolic acids, contributes to the bacterium’s low permeability. This makes Mycobacterium tuberculosis resistant to many common antibiotics. Therefore, drugs like ethambutol, which specifically target this unique structure, are used for effective treatment.
The Core Mechanism: Blocking Cell Wall Synthesis
Ethambutol’s primary function is to disrupt the formation of the mycobacterial cell wall, specifically by interfering with the arabinogalactan layer. It achieves this by inhibiting a group of bacterial enzymes known as arabinosyl transferases, primarily EmbA, EmbB, and EmbC.
These enzymes are responsible for polymerizing, or linking together, D-arabinose sugars to construct the arabinogalactan component of the cell wall. By binding to the active site of these transferases, ethambutol prevents the proper addition of arabinose residues to the growing polysaccharide chain. This blockage effectively halts the assembly of the arabinogalactan “rebar” within the cell wall.
The disruption of arabinogalactan synthesis prevents the attachment of the outer mycolic acid layer, leading to a defective and weakened cell wall. This compromised barrier increases the bacterium’s permeability, making it more susceptible to osmotic pressure and hindering its ability to replicate. Ethambutol’s effect stops bacterial multiplication, allowing the host’s immune system to clear the infection.
The weakened cell wall also enhances the penetration of other antitubercular drugs, such as isoniazid and rifampicin. This synergistic effect is why ethambutol is used as part of a multi-drug treatment regimen for tuberculosis.
How Bacteria Develop Resistance
Bacteria can develop resistance to ethambutol, which can lead to treatment failure. The primary mechanism for this resistance involves genetic mutations within the Mycobacterium tuberculosis genome. These mutations commonly occur in the embB gene, which provides the instructions for making the arabinosyl transferase enzyme.
A mutation in the embB gene can alter the shape of the arabinosyl transferase enzyme, particularly at or near the drug-binding site. For instance, mutations at codon 306 of embB, often resulting in a change from methionine to isoleucine or valine, are frequently associated with ethambutol resistance.
This altered enzyme can still perform its function of building the cell wall, but ethambutol can no longer bind to it effectively. As a result, the drug cannot inhibit arabinogalactan synthesis, allowing the bacterium to continue replicating even in the presence of the antibiotic. Such mutations allow the resistant bacterial strains to survive and multiply, undermining the treatment.
Key Side Effect: Optic Neuritis
Optic neuritis is a side effect of ethambutol treatment, involving inflammation of the optic nerve. This nerve transmits visual information from the eye to the brain, and its inflammation can impair vision.
Patients experiencing ethambutol-induced optic neuritis may notice symptoms such as blurred vision, difficulty distinguishing colors, particularly red and green, and a potential loss of central or peripheral vision. These visual changes can vary in severity, ranging from mild blurring to severe vision loss.
This side effect is dose-dependent, meaning higher daily doses or longer durations of treatment increase the risk. While the exact mechanism is not fully understood, it is believed to involve the drug’s interaction with metal ions, potentially leading to mitochondrial toxicity in the optic nerve.
Optic neuritis caused by ethambutol is often reversible if the drug is discontinued promptly upon symptom onset. Visual recovery can occur over weeks to months following cessation of the medication, though some patients may experience permanent visual defects. Regular vision screening by an ophthalmologist, including checks for visual acuity and color perception, is therefore a recommended part of monitoring patients receiving ethambutol therapy.