Simple Strategy for Taming Membrane-Disrupting Antibiotics

Yu, Yuming; Sabulski, Mary J.; Schell, Wiley A.; Pires, Marcos M.; Perfect, John R.; Regen, Steven L.

doi:10.1021/acs.bioconjchem.6b00629

Cited by 10 publications

(18 citation statements)

References 16 publications

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“…These contrast functional outcomes at low and high concentrations are predicted to undergo in vivo , which is unique for AM3. This feature may contribute development of anti-fungal compounds having less side effects 42 – 44 .…”

Section: Discussionmentioning

confidence: 97%

Channel Formation and Membrane Deformation via Sterol-Aided Polymorphism of Amphidinol 3

Iwamoto

Sumino

Shimada

et al. 2017

Sci Rep

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Amphidinol 3 (AM3) is an anti-fungal polyene extracted from a marine dinoflagellate. Here, we examined the ion channel activity and membrane-embedded structure of AM3 using a lipid bilayer method and atomic force microscopy (AFM). AM3 exhibited large-conductance (~1 nS) and non-selective single-channel activity only when sterols were present in the membrane leaflet of the AM3-added side. The variable conductance suggests the formation of a multimeric barrel-stave pore. At high AM3 concentrations, giant-conductance “jumbo” channels (~40 nS) emerged. AFM revealed a thicker raft-like membrane phase with the appearance of a wrinkled surface, in which phase pores (diameter: ~10 nm) were observed. The flip-flop of ergosterol occurred only after the appearance of the jumbo channel, indicating that the jumbo channel induced a continuity between the outer and inner leaflets of the membrane: a feature characteristic of toroidal-like pores. Thus, AM3 forms different types of sterol-aided polymorphic channels in a concentration dependent manner.

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Section: Discussionmentioning

confidence: 97%

Channel Formation and Membrane Deformation via Sterol-Aided Polymorphism of Amphidinol 3

Iwamoto

Sumino

Shimada

et al. 2017

Sci Rep

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“…An entirely different approach that we have devised for improving the selectivity of membrane-disrupting antimicrobial agents in general, and for Amphotericin B in particular, is to reduce the hemolytic activity of aggregated forms via a “taming” strategy [ 28 , 29 ]. In Figure 7 an illustration is shown of our taming concept.…”

Section: Discovery Of a Membrane Rupture And Leakage Dichotomymentioning

confidence: 99%

“…For proof of concept, we synthesized a series of conjugates of Amphotericin B bearing one, and also two, choloyl moieties. In Figure 8 , it is shown that the simplest representative examples in which Amphotericin B has been covalently attached to a single choloyl group using four different spacers, i.e., 2a – d [ 29 ].…”

Section: Discovery Of a Membrane Rupture And Leakage Dichotomymentioning

confidence: 99%

“…This derivative has proven to be a very convenient and stable precursor for the synthesis of a broad series of conjugates of Amphotericin B. Thus, direct condensation of 3 with a family of α,ω-diamines that were monoacylated with cholic acid, followed by deprotection with piperidine afforded the desired conjugates, 2a – d [ 29 ].…”

Section: Discovery Of a Membrane Rupture And Leakage Dichotomymentioning

confidence: 99%

“…Based on this method, the critical aggregation concentration for 2a – d and 4 were all estimated to be ca. 1 µM, which was the same as Amphotericin B, itself [ 28 , 29 ].…”

Section: Discovery Of a Membrane Rupture And Leakage Dichotomymentioning

confidence: 99%

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Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming

Regen

2021

Molecules

Self Cite

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Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule’s tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a “taming” strategy), we found that by covalently attaching one or more facial amphiphiles (“floats”) to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such “monomer control” and “taming” strategies to other membrane-disrupting antimicrobial agents is briefly discussed.

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Deciphering the Biological Activities of Antifungal Agents with Chemical Probes

Fridman

Sakurai

2023

Angewandte Chemie

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The growing number of fungal infections caused by pathogens resistant to one or more classes of antifungal drugs emphasizes the threat that these microorganisms pose to animal and human health and global food security. Open questions remain regarding the mechanisms of action of the limited repertoire of antifungal agents, making it challenging to rationally develop more efficacious therapeutics. In recent years, the use of chemical biology approaches has resolved some of these questions and has provided new promising concepts to guide the design of antifungal agents. By focusing on examples from studies carried out in recent years, this minireview describes the key roles that probes based on antifungal agents and their derivatives have played in uncovering details about their activities, in detecting resistance, and in characterizing the interactions between these agents and their targets.

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Simple Strategy for Taming Membrane-Disrupting Antibiotics

Cited by 10 publications

References 16 publications

Channel Formation and Membrane Deformation via Sterol-Aided Polymorphism of Amphidinol 3

Channel Formation and Membrane Deformation via Sterol-Aided Polymorphism of Amphidinol 3

Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming

Deciphering the Biological Activities of Antifungal Agents with Chemical Probes

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