A Study on the Effect of Quaternization of Polyene Antibiotics’ Structures on Their Activity, Toxicity, and Impact on Membrane Models
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Published:2024-06-29
Issue:7
Volume:13
Page:608
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ISSN:2079-6382
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Container-title:Antibiotics
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language:en
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Short-container-title:Antibiotics
Author:
Omelchuk Olga1ORCID, Tevyashova Anna12ORCID, Efimova Svetlana3ORCID, Grammatikova Natalia1, Bychkova Elena1, Zatonsky George1, Dezhenkova Lyubov1, Savin Nikita4ORCID, Solovieva Svetlana1, Ostroumova Olga3, Shchekotikhin Andrey1ORCID
Affiliation:
1. Gause Institute of New Antibiotics, 11 B. Pirogovskaya, Moscow 119021, Russia 2. School of Science, Constructor University, Campus Ring 1, 28759 Bremen, Germany 3. Institute of Cytology, The Russian Academy of Sciences, 4 Tikhoretsky Ave., St. Petersburg 194064, Russia 4. Research Laboratory of Biophysics, National University of Science and Technology “MISIS”, 4 p.1 Leninsky Pr., Moscow 119049, Russia
Abstract
Polyene antibiotics have been used in antifungal therapy since the mid-twentieth century. They are highly valued for their broad spectrum of activity and the rarity of pathogen resistance to their action. However, their use in the treatment of systemic mycoses often results in serious side-effects. Recently, there has been a renewed interest in the development of new antifungal drugs based on polyenes, particularly due to the emergence of highly dangerous pathogenic strains of fungi, such as Candida auris, and the increased incidence of mucormycosis. Considerable understanding has been established regarding the structure–biological activity relationships of polyene antifungals. Yet, no previous studies have examined the effect of introducing quaternized fragments into their molecular structure. In this study, we present a series of amides of amphotericin B, nystatin, and natamycin bearing a quaternized group in the side chain, and discuss their biological properties: antifungal activity, cytotoxicity, and effects on lipid bilayers that mimic fungal and mammalian cell membranes. Our research findings suggest that the nature of the introduced quaternized residue plays a more significant role than merely the introduction of a constant positive charge. Among the tested polyenes, derivatives 4b, 5b, and 6b, which contain a fragment of N-methyl-4-(aminomethyl)pyridinium in their structure, are particularly noteworthy due to their biological activity.
Funder
Russian Science Foundation
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