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Arzneimittelforschung 2003; 53(8): 590-599
DOI: 10.1055/s-0031-1297154
Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

Antimicrobial Activity of N-Acylphenothiazines and Their Influence on Lipid Model Membranes and Erythrocyte Membranes

Noboru Motohashi
a   Meiji Pharmaceutical University, Kiyose, Tokyo, Japan
,
Masami Kawase
b   Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan
,
Joseph Molnár
c   Faculty of Medicine, Institute of Microbiology, Albert Szent-Györgyi Medical University, Szeged, Hungary
,
Lajos Ferenczy
d   Faculty of Biology, University of Szegedd, Szeged, Hungary
,
Olga Wesolowska
e   Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
,
Andrzej B. Hendrich
e   Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
,
Malgorzata Bobrowska-Hägerstrand
f   Department of Biology, A˚ bo Akademi, A˚ bo/Turku, Finland
,
Henry Hägerstrand
f   Department of Biology, A˚ bo Akademi, A˚ bo/Turku, Finland
,
Krystyna Michalak
e   Department of Biophysics, Wroclaw Medical University, Wroclaw, Poland
› Author Affiliations
Further Information

Publication History

Publication Date:
25 December 2011 (online)

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Summary

The antibacterial activity and influence on lipid model membranes and erythrocyte membranes of 24 N-acylphenothiazines and trifluoperazine were studied.

  • (1) Among 24 phenothiazines, the antimicrobial activity of amino maleates was the highest.

  • (2) The influence of phenothiazines on model liposome and erythrocyte membranes was studied using N-phenyl-1-naphthylamine (NPN) as fluorescence probe. From the three types of phenothiazine substitution (H, Cl, CF3) at position 2, CF3-phenothiazines were the most ef-fective in the interaction with liposomal membranes.

  • (3) As measured by the polarization degree of 1,6-diphenyl-1,3,5-hexatriene (DPH) fluorescence, the alteration of membrane fluidity induced by CF3-phenothiazines was the biggest. Surprisingly, phenothiazines induced stomatocytic shape alterations (invaginations) in erythrocytes and at higher concentrations, also hemolysis of erythrocytes was observed.

  • (4) The microcalorimetic measurements of influence of phenothiazines on thermal behaviour of synthetic lipid systems confirmed the previously obtained results. The main transition temperature and enthalpy of transition of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) were significantly modified by CF3-phenothiazines, suggesting their penetration of the lipid bilayer.

Above results show that phenothiazine maleates were generally more effective than other phenothiazines used in this study.

Zusammenfassung

Antimikrobielle Wirkung von N-Acylphenothiazinen und ihr Einfluß auf Lipidmembranmodelle und die Erythrozytenmembran

Die antibakterielle Wirksamkeit von

N-Acylphenothiazinen und Trifluoparazinen sowie ihr Einfluß auf Lipidmembranmodelle und Erythrozitmembranen wurden untersucht.

  • (1) Von 24 Phenothiazinen zeigten die Aminomaleate die stärkste antimikrobielle Wirkung.

  • (2) Der Einfluß von Phenothiazinen auf Liposomenund Erythrozytenmem-branmodelle wurde mit dem Fluoreszenz-marker N-Phenyl-1-naphtylamin (NPN) untersucht. Dabei zeigten von den drei Substitutionstypen (H, Cl, CF3-Phenothiazine die höchste Wechselwirkung mit den Liposomenmembranen.

  • (3) Am Ausmaß der Polarisation der 1,6-Diphenyl-1,3,5-hexatrien (DPH)-Fluoreszenz war zu erkennen, daß die CF3-Phenothiazine die Membranfluidität am meisten beeinflußten. Überraschenderweise induzierten die Phenothiazine bei den Erythrotyten eine Formveränderung der Stomatozyten und −in höheren Kon-zentrationen −Hämolyse.

  • (4) Mikrokalorimetrische Messungen des Einflusses der Phenothiazine auf das thermale Verhalten synthetischer Lipidsysteme bestätigen frühere Ergebnisse. Die Hauptübergangstemperatur sowie die Übergangsenthalpie von 1,2-Dipalmitoyl-sn-glycero-3-phosphatidylcholin (DPPC) wurden durch die CF3-Phenothiazine signifikant modifiziert, was darauf hinweist, daß sie die Lipiddoppelschicht penetriren. Die Ergebnisse zeigen, daß die Phenothiazinmaleate den übrigen Phenothiazinen in der Wirkung überlegen waren.

Key words

N-Acylphenothiazines, antimicrobioal activity, erythrocyte membrane, lipid model - membrane, liposome