Interaction of cationic antiseptics with cardiolipin-containing model bacterial membranes

Kholina EG1,2, Bozdaganyan ME1,2, Strakhovskaya MG1,2, Kovalenko IB1,2
About authors

1 Federal Scientific and Clinical Center of Specialized Medical Care and Medical Technology of FMBA, Moscow, Russia

2 Lomonosov Moscow State University, Moscow, Russia

Correspondence should be addressed: Ilya B. Kovalenko
Orekhovyi bulvar, 28, Moscow, 115682; moc.liamg@87oknelavoki

About paper

Funding: the research was carried out with the financial support of the Russian Foundation for Basic Research (project № 19-34-90045) and the State assignment "The influence of the lipid composition of bacterial membranes on the processes of interaction with antimicrobial compounds" (code: "Membrane").

Author contribution: Kholina EG — constructing molecular models of studied substances, calculations, manuscript writing; Bozdaganyan ME — calculations, manuscript writing; Strakhovskaya MG — study concept, manuscript writing, analysis of the results; Kovalenko IB — study concept, building a computing infrastructure, manuscript writing, analysis of the results.

Received: 2021-07-19 Accepted: 2021-08-21 Published online: 2021-09-11

Plasma membrane is one of the major targets for cationic antiseptics (CA). The study was aimed to assess molecular effects of CAs of different chemical classes on cardiolipin-containing regions of bacterial plasma membranes. The study was carried out using coarse-grained molecular modeling. Interaction of CAs, such as miramistin, chlorhexidine, picloxidine, and octenidine, with cardiolipin-containing bilayer was assessed based on the CA coarse-grained models. CAs reduced lipid lateral diffusion coefficients and increased the membrane area per lipid. All CAs, except miramistin, reduced the lipid fatty acid chain order parameters. Adding octenidine at a CA : lipid ratio of 1 : 4 resulted in cardiolipin clustering with subsequent pulling the neutral phosphatidylethanolamine molecules out of the model bilayer. It was found that CАs have the potential for sorption to lipid bilayer, causing clustering of negatively charged lipids. Antiseptic octenidine causes formation of cardiolipin microdomains. Abnormal lateral lipid distribution together with pulling out phosphatidylethanolamine molecules can result in increased lipid bilayer permeability. The most significant reduction of cardiolipin lateral diffusion coefficient by 2.8 ± 0.4 times was observed in the presence of CA chlorhexidine at an antiseptic : lipid ratio of 1 : 4.

Keywords: antiseptic, bacterial membrane, molecular modeling, miramistin, chlorhexidine, picloxidine, octenidine