Authors:	Schwiering, Markus Husmann, Matthias Hellmann, Nadja
Title:	P2X-receptor antagonists inhibit the interaction of S. aureus hemolysin A with membranes
Online publication date:	17-Oct-2022
Year of first publication:	2017
Language:	english
Abstract:	The pore forming hemolysin A, Hla, is a major virulence factor of Staphylococcus aureus. apparently, 1–2 pore(s) per cell suffice(s) to cause cell death. accumulated experimental evidence points towards a major role of atp-gated purinergic receptors (p2xr) for hemolysis caused by hla, complement and other pore forming proteins, presumably by increasing membrane permeability. indeed, in experiments employing rabbit erythrocytes, inhibitory concentrations of frequently employed p2xr-antagonists were in a similar range as previously reported for erythrocytes of other species and other toxins. however, hla-dependent hemolysis was not enhanced by extracellular atp, and oxidized adenosinetriphosphate (oxatp) had only a minor inhibitory effect. unexpectedly, p2xr-inhibitors also prevented hla-induced lysis of pure lipid membranes, demonstrating that the inhibition did not even depend on the presence of p2xr. fluorescence microscopy and gel-electrophoresis clearly revealed that p2xr-inhibitors interfere with binding and subsequent oligomerisation of hla with membranes. similar results were obtained employing hacat-cells. furthermore, calorimetric data and hemolysis experiments with hla pre-treated with pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (ppads) showed that this compound directly binds to hla. our results call for a critical re-assessment of the appealing concept, which suggests that p2xr are general amplifiers of damage by pore-forming proteins.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin FB 09 Chemie, Pharmazie u. Geowissensch.
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8055
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Toxins 9 10
Pages or article number:	Art. 332
Publisher:	MDPI
Publisher place:	Basel
Issue date:	2017
ISSN:	2072-6651
Publisher URL:	http://dx.doi.org/10.3390/toxins9100332
Publisher DOI:	10.3390/toxins9100332
Appears in collections:	DFG-OA-Publizieren (2012 - 2017)