Polyene Antibiotics

Polyene macrolide antibiotics isolated from Streptomyces Gram-positive bacteria have been identified as antifungal agents presenting a very low antibacterial activity. Amphotericin B (AmB) and nystatin (Fig. 1), are two representative members of this class of compounds that continue to play a major role in the treatment of systemic and superficial fungal infections, respectively. However, their utilization implies severe side effects that have restricted their use as antifungal agents and promoted the development of various liposomal formulations to minimize these problems.

Figure 1 - Structures of some polyene antibiotics.

The polyene macrolide antibiotics are known to exert their antibiotic activity via permeabilization of the target plasma membrane of the antibiotic-sensitive organisms leading to a leakage of ions and small molecules, ultimately causing cell destruction. It has been shown that these molecules are able to self-aggregate and form large conductance pores (Fig. 2) with size-discriminating properties in model membrane systems, as well as single ion channels in planar lipid bilayers (BLM). However, the molecular details of the mechanism of antibiotic interaction with, insertion into and final organization within the membranes are still not clear. Particularly, one of the most intriguing questions related to this class of compounds that still persists today is the elucidation of the role of sterols - cholesterol and ergosterol - in their mode of action.

Figure 2 - Schematic representation of the main stages of nystatin interaction with a model system of membranes. After adsorption to the membrane interface (top), the antibiotics self-associate in a pore structure (bottom), when the surface concentration is higher than a critical value. The structures formed in the biological membranes are most probably mixed antibiotic-sterol aggregates.

Our group has taken advantage of the intrinsic fluorescence properties of some of these antibiotics to carry out both steady-state and time-resolved fluorescence studies of their interaction with phospholipid bilayer membranes. We are interested to probe both the structure and activity of the antibiotic species formed under different lipid compositions and sterol content. Insights regarding the structure of the active species formed within the lipid bilayer could significantly advance our understanding about the mode of action of these antibiotics, eventually allowing for the design of more selective and less toxic compounds.

go back to Research Interests