PDR-FNRS application °: 19471108

Title: “Novel amphiphilic neamine and neosamine derivatives: antibacterials targeting bacterial membrane lipids and lipid domains”
Promotors: Marie-Paule Mingeot-Leclercq (LDRI-UCL), Magali Deleu, Laurence Lins

Regarding bacterial membranes, discovering and understanding the mechanism of action of new molecules acting on bacterial membranes is critical. There is an urgent need since the widespread emergence of resistance to antibiotics in pathogenic bacteria over the past 30 years is now a serious threat to global public health. Paradoxically, as the problems accompanying the emergence of resistance to existing drugs increase, there has been a decline in the discovery and development of new antibiotics.

In order to circumvent the resistance mechanisms, works have explored the potential of (poly)cationic amphiphiles, to act as antimicrobial agents. Widely varying in structure and size, all amphiphilic derivatives are based on two common features: a hydrophobic face that interacts with the lipid bilayer and a polar cationic face that is dedicated to interact via electrostatic interactions to anionic moieties such as some lipid headgroups and nucleic acids. Little in vitro resistance to these amphiphiles has been observed, due to their multiples modes of action and ability to form pores in the bacterial membranes. In the search for new antibacterials, amphiphilic aminoglycosides like neamine derivatives have been recently synthesized and some of them showed strong antibacterial activities through the addition to aminoglycoside scaffolds of lipophilic tails.

Results we already obtained have shown that the introduction of naphthylmethylene groups on the neamine backbone shifts the mechanism of action from an intracellular target mechanism to a membrane target effect. Such a target is particularly interesting since it is unlikely to be susceptible to existing mechanisms of bacterial resistance.

In this FNRS-FRS project, we aim to explore the molecular mechanisms involved in the antibacterial activity of new amphiphilic neamine derivatives acting on bacterial membranes.

The objectives are (i) to establish structure/activity relationships with regard to toxicity (ii) to characterize at the molecular level the interaction between neamine compounds with specific lipids or lipid domains.
Different biophysical techniques on liposomes or on lipid monolayers will be used, as well as complementary in silico approaches predicting the molecular features important for optimal lipid/drug interactions. These properties will be correlated to the antimicrobial activity and efflux of the drugs on different P. Aeruginosa strains from clinical origin.