Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines

Melissa M Cadelis (1) , Elliot I W Pike (1) , Weirong Kang , Zimei Wu , Marie-Lise Bourguet-Kondracki (2) , Marine Blanchet (3) , Nicolas Vidal (4) , Jean Michel Brunel (3) , Brent R Copp (1)

1 School of Chemical Sciences [Auckland]
2 MCAM - Molécules de Communication et Adaptation des Micro-organismes
3 MCT - Membranes et cibles thérapeutiques
4 YELEN

A series of substituted di-indolglyoxylamido-spermine analogues were prepared and evaluated for intrinsic antimicrobial properties and the ability to enhance antibiotic action. As a compound class, intrinsic activity was typically observed towards Gram-positive bacteria and the fungus Cryptococcus neoformans, with notable exceptions being the 5-bromo-and 6-chloro-indole analogues which also exhibited modest activity (MIC 34-50 µM) towards the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae. Several analogues enhanced the activity of doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, E. coli, K. pneumoniae and Acinetobacter baumannii. Of particular note was the identification of five antibiotic enhancing analogues (5-Br, 7-F, 5-Me, 7-Me, 7-OMe) which also exhibited low to no cytotoxicity and red blood cell haemolytic properties. The mechanisms of action of the 5-Br and 7-F analogues were attributed to the ability to disrupt the integrity of, and depolarize, bacterial membranes.

Mots clés: Polyamine; indole; indolglyoxylamide; potentiation; antimicrobial

Domaines: Chimie

Melissa M Cadelis, Elliot I W Pike, Weirong Kang, Zimei Wu, Marie-Lise Bourguet-Kondracki, et al.. Exploration of the antibiotic potentiating activity of indolglyoxylpolyamines. European Journal of Medicinal Chemistry, 2019, 183, pp.111708. ⟨10.1016/j.ejmech.2019.111708⟩. ⟨hal-03020885⟩