Abstract
A series of amides of the antifungal antibiotic amphotericin B (AmB) and its conjugates with benzoxaboroles was tested to determine whether they form pores in lipid bilayers and to compare their channel characteristics. The tested derivatives produced pores of larger amplitude and shorter lifetime than those of the parent antibiotic. The pore conductance was related to changes in the partial charge of the hydrogens of the hydroxyl groups in the lactone ring that determined the anion coordination in the channel. Neutralization of one of the polar group charges in the AmB head during chemical modification produced a pronounced effect by diminishing the dwell time of the polyene channel compared to modification of both groups. In this study, compounds that had a modification of one carboxyl or amino group were less effective in initializing phase separation in POPC-membranes compared to derivatives that had modifications of both polar groups as well as the parent antibiotic. The effects were attributed to the restriction of the aggregation process by electrical repulsion between charged derivatives in contrast to neutral compounds. The significant correlation between the ability of derivatives to increase the permeability of model membranes—causing the appearance of single channels in lipid bilayers or inducing calcein leakage from unilamellar vesicles—and the minimal inhibitory concentration indicated that the antifungal effect of the conjugates was due to pore formation in the membranes of target cells.
Highlights
In recent decades, the problem of treating infectious diseases caused by fungal infection has grown due to an increase in immunosuppressed patients and development of antibiotic resistance
Using the quantum-chemical semi empirical method AM1, we evaluated the partial charges of the hydrogens of these ligand groups of amphotericin B (AmB) and its derivatives (Table 2)
The first experimental evidence was obtained of the significant effect of the chemical modification of the charged groups in the head of the AmB molecule on the translocation barrier to the anion through the channel formed by polyene
Summary
The problem of treating infectious diseases caused by fungal infection has grown due to an increase in immunosuppressed patients and development of antibiotic resistance. Polyene macrolide antibiotics, such as amphotericin B and nystatin, have been widely applied in medicine to treat surface and deep mycoses due to their high activity [1]. It is believed that the mechanisms of action of amphotericin B (AmB) and nystatin are related to pore formation in the fungal cell membrane [2,3,4,5,6,7,8,9,10] Due to their poor selectivity towards membranes of fungal vs mammalian cells, polyene macrolides are the most toxic clinically used drugs, which substantially limits their pharmacological application.
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