Investigation of α,ω-Disubstituted Polyamine-Cholic Acid Conjugates Identifies Hyodeoxycholic and Chenodeoxycholic Scaffolds as Non-Toxic, Potent Antimicrobials

Abstract

With the increased incidence of antibiotic resistance, the discovery and development of new antibacterials is of increasing importance and urgency. The report of the natural product antibiotic squalamine in 1993 has stimulated a lot of interest in the study of structurally simplified cholic acid-polyamine derivatives. We report the synthesis of a focused set of deoxycholic acid-polyamine conjugates and the identification of hyodeoxycholic acid derivatives as being potently active towards S. aureus MRSA and some fungal strains, but with no attendant cytotoxicity or hemolytic properties. Analogue 7e exhibited bactericidal activity towards a range of Gram-positive bacteria, while preliminary investigation of its mechanism of action ruled out the bacterial membrane as being a primary cellular target as determined using an ATP-release bioluminescence assay.

Polyamine–Drug Conjugates: Do They Boost Drug Activity?

“…In this case, the hyodeoxycholic acid analogue 47 (Figure 13) exhibited remarkable Gram-positive antibacterial (MIC ≤ 0.20 µM in S. aureus strains) and antifungal activity (MIC ≤ 0.20 µM in C. albicans and MIC = 0.80 µM in C. neoformans) and was devoid of any cytotoxic or hemolytic effects at the top dose tested (32 µg/mL). The bactericidal properties of 47 were also confirmed in several bacterial strains, albeit its exact mechanism of action has still to be elucidated, while membrane perturbation/ATP depletion and antibiotic enhancement have been ruled out [92].…”