Tackling antibiotic resistance using cubosomes

Why?

As a result of decades of misuse of antibiotics, the number of bacteria resistant to commercially available antibiotics is increasing worldwide and is one of the major challenges facing global health. A unique drug-delivery system has been tested in vitro to understand its effect on bacteria.

Antimicrobial peptides (AMPs) are host defense peptides present as part of the innate immune system in virtually all life forms and are being considered a potential treatment for bacterial infections. However, as AMPs often exhibit antibacterial activity across a broad spectrum, they have a limited capacity to induce any significant resistance, as a result of millions of years of co-evolution alongside bacteria.

LL-37 is an important AMP found in humans as part of the innate immune system and recent studies have shown that this peptide can be incorporated into cubic liquid crystalline nanoparticles known as cubosomes. Cubosomes have already shown great promise as a delivery system for pharmaceuticals. Their well-organised internal structure consisting of alternating hydrophilic and hydrophobic domains means they are compatible with both water soluble, insoluble and amphipathic molecules. These cubosomes are able to protect LL-37 from enzymatic degradation by human and bacterial elastases, which has previously limited its therapeutic use. However, the bactericidal mechanisms of cubosomes loaded with LL-37 is not fully understood.

How?

As a result of decades of misuse of antibiotics, the number of bacteria resistant to commercially available antibiotics is increasing worldwide and is one of the major challenges facing global health. A unique drug-delivery system has been tested in vitro to understand its effect on bacteria.

Antimicrobial peptides (AMPs) are host defense peptides present as part of the innate immune system in virtually all life forms and are being considered a potential treatment for bacterial infections. However, as AMPs often exhibit antibacterial activity across a broad spectrum, they have a limited capacity to induce any significant resistance, as a result of millions of years of co-evolution alongside bacteria.

LL-37 is an important AMP found in humans as part of the innate immune system and recent studies have shown that this peptide can be incorporated into cubic liquid crystalline nanoparticles known as cubosomes. Cubosomes have already shown great promise as a delivery system for pharmaceuticals. Their well-organised internal structure consisting of alternating hydrophilic and hydrophobic domains means they are compatible with both water soluble, insoluble and amphipathic molecules. These cubosomes are able to protect LL-37 from enzymatic degradation by human and bacterial elastases, which has previously limited its therapeutic use. However, the bactericidal mechanisms of cubosomes loaded with LL-37 is not fully understood.

Who?

The work was done in a collaboration between researchers at RISE Research Institutes of Sweden, Lund University, University of Copenhagen, Uppsala University, Chalmers University of Technology and ISIS Neutron and Muon Source. ISIS Neutron and Muon Source (RB number: 1810031 DOI:10.5286/ISIS.E.92922658) is acknowledged for beamtime allocation from the Science and Technology Facilities Council. Financial support was obtained from the European Union’s Seventh Framework Program grant agreement No. 604182 within the FORMAMP project and from RISE Research Institutes of Sweden (Stockholm, Sweden). Financial support is also acknowledged from the LEO Foundation Center for Cutaneous Drug Delivery (grant number 2016-11- 01) and MAX4ESSFUN (grant number CTH-009).

"Peptide-Loaded Cubosomes Functioning as an Antimicrobial Unit against Escherichia coli"

ACS Appl. Mater. Interfaces 2019, 11, 24, 21314–21322

The full paper can be found at DOI: 10.1021/acsami.9b01826

What is next?

The findings of this research suggest that LL-37 loaded cubosomes form an antibacterial unit, potentially altering gram-negative bacteria in a lethal way, whilst protecting the LL-37 from enzymatic degradation. Although further in vivo studies are needed to evaluate the clinical relevance of cubosomes as a drug delivery system, the results from this study suggest that the cubosome-bacteria interaction is of a significant importance for the killing of bacteria and the antibiotic crisis.

Figure 1. Schematic of the exposure of bilayers to different drug delivery systems.

Contact:

Maja Hellsing, RISE Research Institutes of Sweden
maja.hellsing @ri.se