Amphotericin B (AmB) is a well known antifungal and antiprotozoal antibiotic used in the clinic for several decades. Clinical applications of AmB, however, are limited by its nephrotoxicity and many other acute side effects which are not acceptable by patients when their life is not threaten. In order to improve the therapeutic index of this drug, lipid formulations have been introduced and many efforts have been made to obtain less toxic AmB derivatives by chemical modifications of the parent drug. This review presents concise knowledge about this fascinating compound and a critical review of the data published within last few years about the mechanism of action of this antibiotic. In particular, in the present work we discuss: i) structure and properties of AmB and its recently synthesized new derivatives; ii) antifungal and antileishmanial activity and toxicity of these compounds; and iii) mode of action of AmB and its derivatives at cellular and molecular levels, with particular attention paid to interactions of AmB and different components of cellular membranes.

Amphotericin B is a powerful but toxic antifungal antibiotic that is used to treat systemic infections. It forms ionic membrane channels in fungal cells. These antibiotic/sterol channels are responsible for the leakage of ions, which causes cell destruction. The detailed molecular properties and structure of amphotericin B channels are still unknown. In the current study, two molecular dynamic simulations were performed of a particular model of amphotericin B/cholesterol channel. The water and phospholipid environment were included in our simulations, and the results obtained were compared with available experimental data. It was found that it is mainly the hydrogen bonding interactions that keep the channel stable in its open form. Our study also revealed the important role of the intermolecular interactions among the hydroxyl, amino, and carboxyl groups of the channel-forming molecules; in particular, some hydroxyl groups stand out as new “hot spots” that are potentially useful for chemotherapeutic investigations. Our results also help to clarify why certain antibiotic derivatives, with a blocked amino group, are less active. We present a hypothesis for the role of membrane lipids and cholesterol in the channel.