TY - JOUR
T1 - Recognition of membrane sterols by polyene antifungals amphotericin B and natamycin, A 13 C MAS NMR study
AU - Ciesielski, Filip
AU - Griffin, David C.
AU - Loraine, Jessica
AU - Rittig, Michael
AU - Delves-Broughton, Joss
AU - Bonev, Boyan B.
N1 - Publisher Copyright:
© 2016 Ciesielski, Griffin, Loraine, Rittig, Delves-Broughton and Bonev.
PY - 2016/6/17
Y1 - 2016/6/17
N2 - The molecular action of polyene macrolides with antifungal activity, amphotericin B and natamycin, involves recognition of sterols in membranes. Physicochemical and functional studies have contributed details to understanding the interactions between amphotericin B and ergosterol and, to a lesser extent, with cholesterol. Fewer molecular details are available on interactions between natamycin with sterols. We use solid state 13 C MAS NMR to characterize the impact of amphotericin B and natamycin on mixed lipid membranes of DOPC/cholesterol or DOPC/ergosterol. In cholesterol-containing membranes, amphotericin B addition resulted in marked increase in both DOPC and cholesterol 13 C MAS NMR linewidth, reflecting membrane insertion and cooperative perturbation of the bilayer. By contrast, natamycin affects little either DOPC or cholesterol linewidth but attenuates cholesterol resonance intensity preferentially for sterol core with lesser impact on the chain. Ergosterol resonances, attenuated by amphotericin B, reveal specific interactions in the sterol core and chain base. Natamycin addition selectively augmented ergosterol resonances from sterol core ring one and, at the same time, from the end of the chain. This puts forward an interaction model similar to the head-to-tail model for amphotericin B/ergosterol pairing but with docking on opposite sterol faces. Low toxicity of natamycin is attributed to selective, non-cooperative sterol engagement compared to cooperative membrane perturbation by amphotericin B.
AB - The molecular action of polyene macrolides with antifungal activity, amphotericin B and natamycin, involves recognition of sterols in membranes. Physicochemical and functional studies have contributed details to understanding the interactions between amphotericin B and ergosterol and, to a lesser extent, with cholesterol. Fewer molecular details are available on interactions between natamycin with sterols. We use solid state 13 C MAS NMR to characterize the impact of amphotericin B and natamycin on mixed lipid membranes of DOPC/cholesterol or DOPC/ergosterol. In cholesterol-containing membranes, amphotericin B addition resulted in marked increase in both DOPC and cholesterol 13 C MAS NMR linewidth, reflecting membrane insertion and cooperative perturbation of the bilayer. By contrast, natamycin affects little either DOPC or cholesterol linewidth but attenuates cholesterol resonance intensity preferentially for sterol core with lesser impact on the chain. Ergosterol resonances, attenuated by amphotericin B, reveal specific interactions in the sterol core and chain base. Natamycin addition selectively augmented ergosterol resonances from sterol core ring one and, at the same time, from the end of the chain. This puts forward an interaction model similar to the head-to-tail model for amphotericin B/ergosterol pairing but with docking on opposite sterol faces. Low toxicity of natamycin is attributed to selective, non-cooperative sterol engagement compared to cooperative membrane perturbation by amphotericin B.
KW - Antifungals
KW - Antimicrobials
KW - C solid state MAS NMR
KW - Cholesterol
KW - Ergosterol
KW - Membranes
KW - Receptor recognition
UR - http://www.scopus.com/inward/record.url?scp=85062199481&partnerID=8YFLogxK
U2 - 10.3389/fcell.2016.00057
DO - 10.3389/fcell.2016.00057
M3 - Article
AN - SCOPUS:85062199481
SN - 2296-634X
VL - 4
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
IS - JUN
M1 - 57
ER -