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Highlights from

The European Congress of Clinical Microbiology & Infectious Diseases

29th Annual Meeting

Amsterdam 13-16 April 2019

Host-defence peptides: a possible alternative to antibiotics?

Take-home messages
  • Host-defence peptides are a natural part of the innate immune system in multi-cellular organisms; they have antimicrobial and immune-modulatory effects
  • Researchers are creating synthetic versions of host-defence peptides
  • The host-defence peptide TCP-25 has entered clinical trials
“Current treatments like antibiotics and antiseptics just address part of the problem and that’s the bacterial part. HDPs also act on the immune system.”

Dr Mariena van der Plas, Associate Professor, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen, Denmark

The rise in multi-drug antibiotic resistance combined with a lack of new antibiotics in development has created an urgent need for novel strategies to combat bacterial infection, according to research presented at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2019, Amsterdam, the Netherlands.

In this session, Dr Mariena van der Plas, Associate Professor, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen, Denmark, outlined how host-defence peptides/ proteins (HDPs) could help in the fight against antibiotic-resistant bacterial disease.

HDPs (also known as antimicrobial peptides, AMPs) are a natural part of the innate immune system, where they provide a first-line of defence against invading microbes. They perform a wide range of functions, from killing invading pathogens to modulating immunity and other biological responses.

Examples of HDPs include cytokines, growth factors, fibrin-bound proteins, protease inhibitors and proteins involved in the blood coagulation system.

Although HDPs are structurally diverse, they do share some common features. They tend to be cationic, interact with bacterial membranes, have broad-spectrum anti-bacterial action and anti-fungal properties. They are associated with low levels of anti-bacterial resistance and have immunomodulatory effects.

Researchers are creating synthetic versions of HDPs in an attempt to harness these effects.

“Current treatments like antibiotics and antiseptics just address part of the problem and that's the bacterial part,” explained Dr van der Plas. “However, HDPs also act on the immune system.”

She continued, “If you think about sepsis, patients don’t die from a bacterial infection, they actually die from the immune system in the end. This is why, not only do we need to fight the infection, at the same time we also need to need to get the immune system to actually balance it out.”

Dr van der Plas' laboratory conducts research into thrombin, an enzyme involved in blood clotting that catalyses the conversion of fibrinogen to fibrin. Proteolysis of thrombin generates several HDPs known as thrombin-derived C-terminal peptides (TCPs). TCPs are naturally found at infection sites such as wounds, where they protect against sepsis.

Research has shown that larger (11 kDa) TCPs can aggregate bacteria and pathogen-associated molecular patterns (PAMPs). Smaller (2kDa) TCPs can scavenge PAMPs, modulate pro-inflammatory markers and have antimicrobial actions.

TCP-25 is an HDP that is currently being researched as a potential antibacterial treatment. It has been shown to effectively disrupt bacterial membranes by binding to bacterial liposaccharides (LPS) and block pro-inflammatory signalling, among other actions. Studies showed that applying a TCP-25 gel can prevent wound infections in mice. It will enter clinical studies later this year.

The antibacterial and immunomodulatory activity of HDPs can also be enhanced, either by directly manipulating peptides or using peptide delivery systems.

One example of HDP modification is tryptophan end-tagging, which promotes bacterial membrane binding and destabilisation.

Peptide delivery systems are being developed. These may increase stability of HDPs, reduce associated toxicity, provide sustained-release action and enable penetration of biofilms.

Peptide delivery systems include microgels and surface coatings, which allow controlled release of HDPs and protect from the HDP from proteolysis, polyethylene glycol conjugation, which may reduce serum protein interaction and proteolysis, and nanoclays, which can help to aggregate bacteria and confine the infection.

Dr van der Plas concluded her presentation by underlining the benefits of HDPs as an antibacterial treatment. In particular, they enforce natural mechanisms in the body, are endogenous structures so are non-toxic compared to antibiotics, have modulatory rather than blocking effects and have multiple targets, including bacterial and fungal targets and the immune system, and have a low resistance risk. She hopes that HDPs will be used to prevent infection, for example directly after surgery.

Based on van der Plas M. Novel peptide-based anti-infective concepts for a post-antibiotic era (symposium S0332). Presented on Saturday 13 April 2019.

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