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Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular
Shahin Sowlati-Hashjin1,2, Paola Carbone3, Mikko Karttunen1,2,4
1Department of Chemistry, The University of Western Ontario, 1151 Richmond Street, London, Ontario N6A 5B7, Canada.
Abstract:
Polyhexamethylene biguanide (PHMB) is a cationic polymer with antimicrobial and antiviral properties. It has been commonly accepted that the antimicrobial activity is due to the ability of PHMB to perforate the bacterial phospholipid membrane leading ultimately to its death. In this study, we show by the means of atomistic molecular dynamics (MD) simulations that, while the PHMB molecules attach to the surface of the phospholipid bilayer and partially penetrate it, they do not cause any pore formation at least within the microsecond simulation times. The polymers initially adsorb onto the membrane surface via the favorable electrostatic interactions between the phospholipid headgroups and the biguanide groups and then partially penetrate the membrane slightly disrupting its structure. This, however, does not lead to the formation of any pores. The microsecond-scale simulations reveal that it is unlikely for PHMB to spontaneously pass through the phospholipid membrane. Our findings suggest that PHMB translocation across the bilayer may take place through binding to the phospholipids. Once inside the cell, the polymer can effectively "bind" to DNA through extensive interactions with DNA phosphate backbone, which can potentially block the DNA replication process or activate DNA repair pathways.
Insights
Polyhexamethylene biguanide (PHMB) attaches to cell membranes but does not form pores, challenging previous theories. Simulations suggest PHMB may translocate by binding to phospholipids, potentially affecting DNA replication.
Area of Science:
- Biophysics
- Computational Biology
- Materials Science
Background:
- Polyhexamethylene biguanide (PHMB) is a widely used antimicrobial agent.
- Its mechanism of action is commonly attributed to membrane perforation.
- The precise molecular interactions of PHMB with lipid bilayers remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanism of PHMB interaction with phospholipid bilayers.
- To determine if PHMB causes pore formation in bacterial membranes.
- To elucidate the translocation and intracellular mechanisms of PHMB.
Main Methods:
- Atomistic molecular dynamics (MD) simulations were employed.
- Simulations were conducted over microsecond timescales.
- Analysis focused on polymer-lipid interactions and membrane structural changes.
Main Results:
- PHMB molecules adsorb onto the phospholipid bilayer surface via electrostatic interactions.
- Partial penetration and structural disruption of the membrane occur, but no pores are formed.
- PHMB translocation across the bilayer is unlikely without phospholipid binding.
Conclusions:
- The widely accepted pore formation mechanism for PHMB's antimicrobial activity is challenged.
- PHMB may translocate across membranes by interacting with phospholipids.
- Intracellularly, PHMB binds to DNA, potentially inhibiting replication or activating repair pathways.
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