Hydrophobicity of Cholic Acid-Derived Amphiphiles Dictates the Antimicrobial Specificity.

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 <b>1</b> harboring a methyl group has antimicrobial activity against mycobacterial species. On the other hand, amphiphile <b>7</b> containing an octyl chain was selective against Gram-positive and Gram-negative bacilli. Biochemical assays confirmed the selective membrane permeabilization abilities of amphiphiles <b>1</b> and <b>7</b>. 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.