Simple Strategy for Taming Membrane-Disrupting Antibiotics.

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biochemistry

Background:

• Membrane-disrupting antibiotics are crucial for treating fungal infections.
• Current antibiotics like Amphotericin B (AmB) exhibit significant host toxicity, limiting their clinical use.
• Strategies to enhance cellular selectivity are needed to improve antibiotic safety profiles.

Purpose of the Study:

• To develop a novel strategy for increasing the cellular selectivity of membrane-disrupting antibiotics.
• To evaluate the impact of attaching a facially amphiphilic sterol to Amphotericin B (AmB) on its activity and toxicity.

Main Methods:

• Covalent attachment of cholic acid, a sterol, to Amphotericin B via α,ω-diamine linkers.
• Assessment of hemolytic activity (red blood cell lysis).
• Evaluation of cytotoxicity against HEK293T cells.
• Measurement of retained antifungal activity against relevant fungal pathogens.

Main Results:

• The modified Amphotericin B (AmB) derivatives showed a dramatic reduction in hemolytic activity.
• Significant decrease in toxicity toward HEK293T cells was observed.
• Substantial retention of antifungal activity was maintained in the modified compounds.

Conclusions:

• Attaching a facially amphiphilic sterol to membrane-disrupting antibiotics is an effective strategy to enhance cellular selectivity.
• This approach significantly reduces host toxicity and red blood cell damage while preserving therapeutic antifungal efficacy.
• The developed strategy holds promise for creating safer and more effective antifungal agents.