1. Biochim Biophys Acta Biomembr. 2019 Oct 1;1861(10):182998. doi:
10.1016/j.bbamem.2019.05.020. Epub 2019 May 31.

Antimicrobial activity of amphiphilic neamine derivatives: Understanding the
mechanism of action on Gram-positive bacteria.

Swain J(1), El Khoury M(1), Flament A(1), Dezanet C(2), Briée F(2), Van Der
Smissen P(3), Décout JL(2), Mingeot-Leclercq MP(4).

Author information: 
(1)Université catholique de Louvain, Louvain Drug Research Institute,
Pharmacologie Cellulaire et Moléculaire, avenue E. Mounier 73, UCL B1.73.05, 1200
Brussels, Belgium.
(2)Université Grenoble Alpes/CNRS, Département de Pharmacochimie Moléculaire, rue
de la Chimie, F-38041 Grenoble, France.
(3)Université catholique de Louvain, de Duve Institute, avenue Hippocrate 75, UCL
B1.75.05, 1200, Brussels, Belgium.
(4)Université catholique de Louvain, Louvain Drug Research Institute,
Pharmacologie Cellulaire et Moléculaire, avenue E. Mounier 73, UCL B1.73.05, 1200
Brussels, Belgium. Electronic address: marie-paule.mingeot@uclouvain.be.

Amphiphilic aminoglycoside derivatives are potential new antimicrobial agents
mostly developed to fight resistant bacteria. The mechanism of action of the
3',6-dinonyl neamine, one of the most promising derivative, has been investigated
on Gram-negative bacteria, including P. aeruginosa. In this study, we have
assessed its mechanism of action against Gram-positive bacteria, S. aureus and B.
subtilis. By conducting time killing experiments, we assessed the bactericidal
effect induced by 3',6-dinonyl neamine on S. aureus MSSA and MRSA. By measuring
the displacement of BODIPY™-TR cadaverine bound to lipoteichoic acids (LTA), we
showed that 3',6-dinonyl neamine interacts with these bacterial surface
components. We also highlighted the ability of 3',6-dinonyl neamine to enhance
membrane depolarization and induce membrane permeability, by using fluorescent
probes, DiSC3C(5) and propidium iodide, respectively. These effects are observed 
for both MSSA and MRSA S. aureus as well as for B. subtilis. By electronic
microscopy, we imaged the disruption of membrane integrity of the bacterial cell 
wall and by fluorescence microscopy, we demonstrated changes in the localization 
of lipids from the enriched-septum region and the impairment of the formation of 
septum. At a glance, we demonstrated that 3',6-dinonyl neamine interferes with
multiple targets suggesting a low ability of bacteria to acquire resistance to
this agent. In turn, the amphiphilic neamine derivatives are promising candidates
for development as novel multitarget therapeutic antibiotics.

Copyright © 2019. Published by Elsevier B.V.

DOI: 10.1016/j.bbamem.2019.05.020 
PMID: 31153908