Investigation of α,ω-Disubstituted Polyamine-Cholic Acid Conjugates Identifies Hyodeoxycholic and Chenodeoxycholic Scaffolds as Non-Toxic, Potent Antimicrobials
Kenneth Sue,
Melissa M. Cadelis,
Thomas Troia,
Florent Rouvier,
Marie-Lise Bourguet-Kondracki,
Jean Michel Brunel,
Brent R. Copp
Affiliations
Kenneth Sue
School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Melissa M. Cadelis
School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
Thomas Troia
UMR MD1 “Membranes et Cibles Therapeutiques”, U1261 INSERM, Faculté de Pharmacie, Aix-Marseille Universite, 27 bd Jean Moulin, 13385 Marseille, France
Florent Rouvier
UMR MD1 “Membranes et Cibles Therapeutiques”, U1261 INSERM, Faculté de Pharmacie, Aix-Marseille Universite, 27 bd Jean Moulin, 13385 Marseille, France
Marie-Lise Bourguet-Kondracki
Laboratoire Molécules de Communication et Adaptation des Micro-Organismes, UMR 7245 CNRS, Muséum National d’Histoire Naturelle, 57 Rue Cuvier (C.P. 54), 75005 Paris, France
Jean Michel Brunel
UMR MD1 “Membranes et Cibles Therapeutiques”, U1261 INSERM, Faculté de Pharmacie, Aix-Marseille Universite, 27 bd Jean Moulin, 13385 Marseille, France
Brent R. Copp
School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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.
