New polyaminoisoprenyl antibiotics enhancers against two multidrug resistant Gramnegative bacteria from Enterobacter and Salmonella species

Jean Michel Bolla (1) , Jean Michel Brunel (1) , Aurélie Lieutaud (1) , Cyril Pieri (1)

1 MCT - Membranes et cibles thérapeutiques

A series consisting of new polyaminoisoprenyl derivatives were prepared in moderate to good chemical yields varying from 32 to 64% according two synthetic pathways: 1) using a titanium reductive amination reaction affording a 50/50 mixture of cis and trans isomers 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.

Keywords: Gram-negative bacteria; Multi-drug resistance; Efflux pump; Antibiotic enhancers; Polyaminoisoprenyl derivatives

Domains: Life Sciences [q-bio]

Jean Michel Bolla, Jean Michel Brunel, Aurélie Lieutaud, Cyril Pieri. New polyaminoisoprenyl antibiotics enhancers against two multidrug resistant Gramnegative bacteria from Enterobacter and Salmonella species. Journal of Medicinal Chemistry, 2020, 63 (18), pp.10496-10508. ⟨10.1021/acs.jmedchem.0c01335⟩. ⟨hal-03220259⟩