Hydrophobicity of Cholic Acid-Derived Amphiphiles Dictates the Antimicrobial Specificity

Abstract

The unique structural components of cell membranes of Gram-positive bacteria, Gram-negative bacteria, and mycobacteria provide an excellent therapeutic target for developing highly specific antimicrobials. Here, we report the synthesis of nine cholic acid (CA)-derived amphiphiles, where three hydroxyl groups of CA were tethered to dimethylamino pyridine and the C24-carboxyl group was conjugated with different alkyl chains. Structure–activity investigations revealed that amphiphile 1 harboring a methyl group has antimicrobial activity against mycobacterial species. On the other hand, amphiphile 7 containing an octyl chain was selective against Gram-positive and Gram-negative bacilli. Biochemical assays confirmed the selective membrane permeabilization abilities of amphiphiles 1 and 7. Importantly, we demonstrate the selective actions of amphiphiles in clearing biofilms, intracellular bacteria, and wound infections. Therefore, for the first time, we show that the unique structural features of CA-derived amphiphiles dictate selective activity against specific bacterial species.

Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma

“…Although BAs have been reported to have both positive and negative effects on the gut microbiota, BAs generally decrease the integrity of bacterial cell membranes, and increase permeability and cell death 68 . The extent of membrane damage depends largely on BA hydrophobicity: higher hydrophobicity is associated with greater detrimental effects on the bacterial membrane 69 . This finding explains why unconjugated BAs often have stronger antibacterial properties than their conjugated counterparts: conjugation markedly decreases lipophilicity 68 .…”