New Polyaminoisoprenyl Antibiotics Enhancers against Two Multidrug-Resistant Gram-Negative Bacteria from Enterobacter and Salmonella Species

A series
consisting of new polyaminoisoprenyl derivatives were
prepared in moderate to good chemical yields varying from 32 to 64%
according to two synthetic pathways: (1) using a titanium-reductive
amination reaction affording a 50/50 mixture of cis and trans isomers
and (2) a direct nucleophilic substitution leading to a stereoselective
synthesis of the compounds of interest. These compounds were then
successfully evaluated for their in vitro antibiotic
enhancer properties against resistant Gram-negative bacteria of four
antibiotics belonging to four different families. The mechanism of
action against Enterobacter aerogenes of one of the most efficient of these chemosensitizing agents was
precisely evaluated by using fluorescent dyes to measure outer-membrane
permeability and to determine membrane depolarization. The weak cytotoxicity
encountered led us to perform an in vivo experiment
dealing with the treatment of mice infected with Salmonella
typhimurium and affording preliminary promising results
in terms of tolerance and efficiency of the polyaminoisoprenyl derivative 5r/doxycycline combination.