Poster Presenter

The Quest For Understanding The Specificity Of Polymyxin-B/Lipid-A Interactions
Murzyn K., Pasenkiewicz-Gierula M.
Poland

With ever increasing incidence of drug-resistant strains of microorganisms there is an urgent need for a new class of antimicrobial agents to which bacteria will not develop resistance. Drugs acting on the bacterial membrane are less likely to induce resistance in microbes than drugs that act on proteins or nucleic acids. Membrane-active antibiotics selectively target bacterial membranes due to marked differences in the lipid make-up of bacterial and animal membranes and distinct molecular composition of cytoplasmatic membranes of Gram-positive (G+) and Gram-negative (G-) bacteria. But even though it is difficult for the bacteria to develop resistance to such antibiotics their selectivity is not sufficient to make them suitable for therapeutic purposes at present.

In general, molecular mechanisms of action of membrane-active compounds (MAC) is inadequately known, in particular, little is known about the molecular basis of their selectivity. Furthermore, in many cases, neither MAC conformation nor localisation in the membrane have been determined.

We apply molecular modelling methodology to elucidate the molecular mechanism of polymyxin-B (PMB) antibacterial activity. PMB is a representative MAC which is believed to interact highly specifically with lipid-A, the fundamental part of the most characteristic bacterial membrane lipid, lipopolisaccharide. We report results of two molecular dynamics simulation studies of lipid-A bilayer (a reference system) and a lipid-A bilayer with several PMB molecules interacting with lipid molecules (a research system). Our goal is to identify unique features of PMB molecule which are responsible for PMB/lipid-A recognition and binding and which influence most strongly the lipid bilayer properties.