Antimicrobial and Lytic Activities of Squalamine Analogs: Effect of Varied Cationic Groups at C3 and Stereochemistry at C7

Abstract

Squalamine (3β-N-1-{N-[3-(4-aminobutyl)]-1,3-diaminopropane}-7α,24R-dihydroxy-5α-cholestane-24-sulfate), an aminosterol from the dogfish shark (Squalus acanthias), is a potent antimicrobial compound believed to act through plasma membrane lysis. In this report, the antimicrobial activity of squalamine, several structurally related analogs, and bile acid based aminosterols are characterized using two different assays. The structurally similar analogs vary in the stereochemistry at the 3- and 7- substitutents, and also in the length and composition of the polyamine added at C-3. The bile acid analogs are generated by the addition of diaminopropane to C-3 of common bile acid methyl esters. The antimicrobial activity of the analogs was assessed against four bacterial strains. Membrane lytic activity was assayed using large unilamellar vesicles encapsulating a fluorescent calcein dye. Both vesicle lysis and antimicrobial activity of the aminosterols are shown to improve with more cationic groups on the polyamine substituent at C-3. Also, analogs with a 7α-OH substitutent are more effective than their 7β-OH analogs. The bile acid analogs were significantly less active than squalamine.The results suggest that the stereochemistry of the C7-OH group and the A/B ring junction is important in aminosterol activation at the membrane surface.