Cholic acid derivatives: novel antimicrobials

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery

Background:

• Development of novel antimicrobial agents is crucial to combat rising resistance.
• Squalamine and polymyxin B (PMB) are known antibiotics with unique structures and mechanisms.

Purpose of the Study:

• To synthesize and evaluate cholic acid-derived mimics of squalamine and polymyxin B (PMB) as potential antimicrobial agents.
• To investigate the structure-activity relationships of these novel compounds.

Main Methods:

• Synthesis of squalamine and PMB mimics from cholic acid.
• Assessment of broad-spectrum antimicrobial activity against Gram-negative and Gram-positive bacteria.
• Evaluation of outer membrane permeabilization in Gram-negative bacteria.
• Analysis of hemolytic activity and serum protein interactions.

Main Results:

• Cholic acid-derived mimics of squalamine and PMB were successfully prepared.
• These mimics exhibit broad-spectrum antimicrobial activity.
• Some mimics effectively permeabilize Gram-negative bacterial outer membranes, increasing sensitivity to hydrophobic antibiotics.
• Certain mimics demonstrate reduced hemolytic activity and improved serum stability.

Conclusions:

• Cholic acid is a viable scaffold for developing novel antimicrobial agents mimicking squalamine and PMB.
• These mimics offer a promising strategy for combating Gram-negative bacterial infections, particularly by overcoming outer membrane barriers.
• Further optimization can yield safe and effective antimicrobial therapeutics with reduced side effects.