title: The Pseudomonas aeruginosa membranes: a target for a new amphiphilic aminoglycoside derivative?
abstract: Aminoglycosides are among the most potent antimicrobials to eradicate Pseudomonas aeruginosa. However, the emergence of resistance has clearly led to a shortage of treatment options, especially for critically ill patients. In the search for new antibiotics, we have synthesized derivatives of the small aminoglycoside, neamine. The amphiphilic aminoglycoside 3',4',6-tri-2-naphtylmethylene neamine (3',4',6-tri-2NM neamine) has appeared to be active against sensitive and resistant P. aeruginosa strains as well as Staphylococcus aureus strains (Baussanne et al., 2010). To understand the molecular mechanism involved, we determined the ability of 3',4',6-tri-2NM neamine to alter the protein synthesis and to interact with the bacterial membranes of P. aeruginosa or models mimicking these membranes. Using atomic force microscopy, we observed a decrease of P. aeruginosa cell thickness. In models of bacterial lipid membranes, we showed a lipid membrane permeabilization in agreement with the deep insertion of 3',4',6-tri-2NM neamine within lipid bilayer as predicted by modeling. This new amphiphilic aminoglycoside bound to lipopolysaccharides and induced P. aeruginosa membrane depolarization. All these effects were compared to those obtained with neamine, the disubstituted neamine derivative (3',6-di-2NM neamine), conventional aminoglycosides (neomycin B and gentamicin) as well as to compounds acting on lipid bilayers like colistin and chlorhexidine. All together, the data showed that naphthylmethyl neamine derivatives target the membrane of P. aeruginosa. This should offer promising prospects in the search for new antibacterials against drug- or biocide-resistant strains.
authors.affiliation: Université catholique de Louvain, Louvain Drug Research Institute, Unité de Pharmacologie Cellulaire et Moléculaire, UCL 73.70, avenue E. Mounier 73, B-1200 Bruxelles, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Ouberai
authors.forename: Farid
authors.initials: F
authors.lastname: El Garch
authors.forename: Antoine
authors.initials: A
authors.lastname: Bussiere
authors.forename: Mickael
authors.initials: M
authors.lastname: Riou
authors.forename: David
authors.initials: D
authors.lastname: Alsteens
authors.forename: Laurence
authors.initials: L
authors.lastname: Lins
authors.forename: Isabelle
authors.initials: I
authors.lastname: Baussanne
authors.forename: Yves F
authors.initials: YF
authors.lastname: Dufrêne
authors.forename: Robert
authors.initials: R
authors.lastname: Brasseur
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Decout
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D005601:Framycetin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development
chemical_list: C559661:3',4',6-tri-2-naphtylmethylene neamine; C559660:3',6-di-2-naphtylmethylene neamine; D000900:Anti-Bacterial Agents; D008051:Lipid Bilayers; D008070:Lipopolysaccharides; D008081:Liposomes; D005601:Framycetin; C488396:neamine