Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane

Tomoya Yamamoto, Yuichi Umegawa, Hiroshi Tsuchikawa, Nobuaki Matsumori, Shinya Hanashima, Michio Murata, Resul Haser, Bernard J. Rawlings, Patrick Caffrey

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K+ flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity.

Original languageEnglish
Pages (from-to)5782-5788
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number17
DOIs
Publication statusPublished - Apr 15 2015

Fingerprint

Amphotericin B
Sterols
Ion Channels
Membranes
Conformations
Polyenes
Macrolides
Hydrogen Bonding
Ketones
Liposomes
Rigidity
polyol
Hydrogen bonds
Fluxes
Anti-Bacterial Agents
Derivatives
Infection

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane. / Yamamoto, Tomoya; Umegawa, Yuichi; Tsuchikawa, Hiroshi; Matsumori, Nobuaki; Hanashima, Shinya; Murata, Michio; Haser, Resul; Rawlings, Bernard J.; Caffrey, Patrick.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 17, 15.04.2015, p. 5782-5788.

Research output: Contribution to journalArticle

Yamamoto, T, Umegawa, Y, Tsuchikawa, H, Matsumori, N, Hanashima, S, Murata, M, Haser, R, Rawlings, BJ & Caffrey, P 2015, 'Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane', Bioorganic and Medicinal Chemistry, vol. 23, no. 17, pp. 5782-5788. https://doi.org/10.1016/j.bmc.2015.07.009
Yamamoto, Tomoya ; Umegawa, Yuichi ; Tsuchikawa, Hiroshi ; Matsumori, Nobuaki ; Hanashima, Shinya ; Murata, Michio ; Haser, Resul ; Rawlings, Bernard J. ; Caffrey, Patrick. / Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 17. pp. 5782-5788.
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