1. Phys Chem Chem Phys. 2017 Nov 15;19(44):30078-30088. doi: 10.1039/c7cp05353c.

The molecular mechanism of Nystatin action is dependent on the membrane
biophysical properties and lipid composition.

Dos Santos AG(1), Marquês JT, Carreira AC, Castro IR, Viana AS, Mingeot-Leclercq 
MP, de Almeida RFM, Silva LC.

Author information: 
(1)iMed.ULisboa - Research Institute for Medicines, Faculdade de Farmácia,
Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.

Nystatin (Nys) is a pore forming broad-spectrum and efficient antifungal drug
with significant toxicity in mammalian organisms. In order to develop a non-toxic
and more effective Nys formulation, its molecular mechanism of action at the cell
membrane needs to be better understood. It is widely accepted that Nys activity
and toxicity depend on the presence and type of membrane sterols. Taking
advantage of multiple biophysical methodologies, we now show that the formation
and stabilization of Nys aqueous pores, which are associated with Nys
cytotoxicity, occur in the absence of membrane sterols. Our results suggest that 
the Nys mechanism of action is driven by the presence of highly ordered membrane 
domains capable of stabilizing the Nys oligomers. Moreover, Nys pore formation is
accompanied by strong Nys-induced membrane reorganization that depends on
membrane lipid composition and seems to underlie the Nys cytotoxic effect.
Accordingly, in membranes enriched in a gel-phase forming phospholipid, Nys
incorporates within the phospholipid-enriched gel domains, where it forms pores
able to expand the gel domains. In contrast, in membranes enriched in gel domain 
forming sphingolipids, Nys-induced pore formation occurs through the
destabilization of the gel phase. These results show that the Nys mechanism of
action is complex and not only dependent on membrane sterols, and provide further
insight into the molecular details governing Nys activity and toxicity.

DOI: 10.1039/c7cp05353c 
PMID: 29098221