Antimicrobial activity of amphiphilic neamine derivatives: Understanding the mechanism of action on Gram-positive bacteria |
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Authors: | Jitendriya Swain Micheline El Khoury Aurélien Flament Clément Dezanet Florian Briée Patrick Van Der Smissen Jean-Luc Décout Marie-Paule Mingeot-Leclercq |
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Affiliation: | 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 |
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Abstract: | 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. |
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Keywords: | Corresponding author. Bacterial membranes Antibiotics Amphiphilic aminoglycosides Gram-positive Lipoteichoic acid Cardiolipin Membrane permeability Membrane depolarization |
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