1. Biochim Biophys Acta. 2011 Jun;1808(6):1716-27. Epub 2011 Feb 1.

The Pseudomonas aeruginosa membranes: A target for a new amphiphilic
aminoglycoside derivative?

Ouberai M, El Garch F, Bussiere A, Riou M, Alsteens D, Lins L, Baussanne I,
Dufrêne YF, Brasseur R, Decout JL, Mingeot-Leclercq MP.

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.

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.

PMID: 21291859  [PubMed - in process]