Membrane permeabilization and perturbation induced by alkyl- biguanidium salts

ABSTRACT

Alkylbiguanidium salts show membrane perturbing properties toward simple phospholipid bilayer (liposomes) and complex phospholipid membranes (bacterial membranes). Compared to metformin and phenformin, alkylbiguanidium salts induce a more significant permeabilization of the phospholipid membranes, leading to highly selective H⁺/OH⁻ ion transport and subsequent depolarization of the membrane. Although alkylbiguanidium salts with shorter C₆ and C₈ chains are too hydrophilic to be inserted into the membrane and perturb it, those with C₁₀, C₁₂, C₁₄, and C₁₆ alkyl chains show high membrane permeabilization and depolarization activity. In addition, the C₁₀, C₁₂, and C₁₄ compounds possess interesting antimicrobial activity, and, at concentrations close to their minimal inhibitory concentrations, they show low hemolytic activity and toxicity.

Graphical Abstract

KEYWORDS:

• Alkylbiguanidium salts
• membrane depolarization
• ion transport
• antibacterial activity

Acknowledgments

We gratefully acknowledge the Canadian Institutes of Health Research (CIHR), Canadian Cancer Society (CCS), Natural Sciences and Engineering Research Council of Canada (NSERC), Fonds Québécois de la Recherche sur la Nature et les Technologies (FRQ-NT), and Fonds Marguerite Ruel pour la Recherché sur le Cancer - Université de Montréal for financial support. We also thank Le Centre Régional de RMN and Le Centre Régional de Spectrométrie de Masse of the Université de Montréal. We thank the Département de Microbiologie, Infectiologie et Immunologie - Université de Montréal for bacterial and fungal strains. We thank Prof. K. Wilkinson and J.N. Pelletier for access to instruments in their laboratories.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. All authors declare no conflict of interest.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

Supplemental data for this can be accessed here.

Additional information

Funding

This work was supported by Canadian Institutes of Health Research (CIHR), Canadian Cancer Society (CCS), Natural Sciences and Engineering Research Council of Canada (NSERC), Fonds Québécois de la Recherche sur la Nature et les Technologies (FRQ-NT), and the Fonds Marguerite Ruel pour la Recherché sur le Cancer - Université de Montréal.