Multiple triclosan targets in Trypanosoma brucei

Area of Science:

• Biochemistry
• Parasitology
• Drug Discovery

Background:

• Trypanosoma brucei possesses genes for fatty acid synthesis enzymes similar to bacterial type II enzymes.
• Triclosan, a known inhibitor of type II enoyl-acyl carrier protein (enoyl-ACP) reductase, was investigated for its effects on T. brucei.

Purpose of the Study:

• To investigate the mechanism of triclosan's anti-trypanosomal activity.
• To determine if triclosan specifically inhibits fatty acid synthesis in T. brucei.

Main Methods:

• Culturing of procyclic and bloodstream forms of T. brucei.
• Assessing the effects of triclosan on parasite viability and cell-free fatty acid synthesis.
• Measuring the incorporation of radiolabeled fatty acids and analyzing fatty acid remodeling and exchange pathways.

Main Results:

• Triclosan demonstrated potent killing of both procyclic and bloodstream forms of T. brucei.
• Triclosan inhibited cell-free fatty acid synthesis but did not affect fatty acid elongation in bloodstream forms.
• Triclosan inhibited fatty acid remodeling and myristate exchange, but these pathways are specific to bloodstream forms, suggesting a broader mechanism of action.

Conclusions:

• Triclosan's killing mechanism in T. brucei may not be solely through enoyl-ACP reductase inhibition.
• Triclosan might exert its effect by non-specifically perturbing subcellular membrane structure.
• This non-specific membrane disruption could lead to the dysfunction of essential membrane-resident biochemical pathways, providing a potential new avenue for anti-parasitic drug development.