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1.D.31 The Amphotericin B (Amphotericin) Family

Amphotericin B (AmB)is an antifungal archetype for small molecules that form transmembrane ion channels (see also TC family 1.D.20). Palacios et al. (2011) reported that a series of functional group-deficient probes have revealed many key underpinnings of the ion channel and antifungal activities of amphotericin B. Specifically, in stark contrast to two leading models, polar interactions between mycosamine and carboxylic acid appendages on neighboring amphotericin B molecules are not required for ion channel formation; nor are these functional groups required for binding to phospholipid bilayers. However, the mycosamine sugar is required for direct binding interactions between amphotericin B and ergosterol and cholesterol. Synthetically deleting this appendage also abolishes ion channel and antifungal activities. A mycosamine-mediated direct binding interaction between amphotericin B and ergosterol is probably required for both forming ion channels and killing yeast cells.

AmB self-assembles in lipid membranes with the polyol region lining a channel interior that funnels to its narrowest region at the C3-hydroxyl group. The C3-hydroxyl group was deleted, and the resulting derivative, C3deoxyAmB (C3deOAmB) was found to possess the same macrocycle conformation as AmB. It retains the capacity to form transmembrane ion channels, yet the conductance was threefold lower than that of AmB channels (Davis et al. 2015). Amphotericin probably promotes the formation of membrane toroidal pores (Falcón-González et al. 2017). AmB resides inside cell membranes and is highly ordered; its orientation is primarily parallel to phospholipid acyl chains, supporting the ion channel model (Dong et al. 2021). An analytical platform can be used for developing low-toxicity, resistance-refractory antifungal agents.

References associated with 1.D.31 family:

Davis SA., Della Ripa LA., Hu L., Cioffi AG., Pogorelov TV., Rienstra CM. and Burke MD. (2015). C3-OH of Amphotericin B Plays an Important Role in Ion Conductance. J Am Chem Soc. 137(48):15102-4. 26580003
Dong, P.T., C. Zong, Z. Dagher, J. Hui, J. Li, Y. Zhan, M. Zhang, M.K. Mansour, and J.X. Cheng. (2021). Polarization-sensitive stimulated Raman scattering imaging resolves amphotericin B orientation in membrane. Sci Adv 7:. 33523971
Falcón-González, J.M., G. Jiménez-Domínguez, I. Ortega-Blake, and M. Carrillo-Tripp. (2017). Multi-Phase Solvation Model for Biological Membranes: Molecular Action Mechanism of Amphotericin B. J Chem Theory Comput. [Epub: Ahead of Print] 28553993
Palacios, D.S., I. Dailey, D.M. Siebert, B.C. Wilcock, and M.D. Burke. (2011). Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities. Proc. Natl. Acad. Sci. USA 108: 6733-6738. 21368185