Pore-forming activity of new conjugate antibiotics based on amphotericin B

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.

<p>Synthesis, characterization, and mechanistic studies of a gold nanoparticle–amphotericin B covalent conjugate with enhanced antileishmanial efficacy and reduced cytotoxicity</p>

“…Therefore, water-stable and well-dispersed aqueous solutions of AmB with low toxicity and reduced manufacturing costs remain a priority. New derivatives of AmB for improved water solubility, antifungal efficacy, and reduced cytotoxicity were synthesized 52,72–74. In general, the single amine and single carboxylic group of AmB were preferred for chemical modification75,76 where modification of the AmB amine group was found to be more effective in reducing the cytotoxicity77 without compromising efficacy52 against fungus.…”

Sterol Sponge Mechanism Is Conserved for Glycosylated Polyene Macrolides

“…12 , 13 , 17 This mechanism continues to appear in modern textbooks and publications, including by groups aiming to improve the pharmaceutical properties of AmB or other GPMs. 18 − 22 However, recent studies have decoupled ion channel formation from the fungicidal activity of AmB and shown that only glycosylation-dependent ergosterol sequestration is essential. 9 , 15 , 23 Specifically, a synthetic derivative of AmB lacking a C35 hydroxyl group did not form ion channels but retained ergosterol binding and fungicidal activity.…”

Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

“…Moreover, benzoxaboroles are known to enhance the transport of macromolecules into the cell as a result of the interaction with 1,2- and 1,3-diol polysaccharides located on the cell surface. These properties, as well as the ability of some heterocyclic boronic acids and benzoxaborole derivatives to exhibit activity against Gram-negative bacteria with multi-drug resistance, were considered when developing chimeric antibiotics based on glycopeptides or polyene macrocyclic antibiotics containing benzoxaboroles in their structure [ 6 , 12 ] and benzoxaborole derivatives of azithromycin [ 8 ].…”