The Microbe Killers of the Future: Cationic Host Defense Peptides!

Mookherjee, N., Anderson, M.A., Haagsman, H.P. et al. Antimicrobial host defence peptides: functions and clinical potential. Nat Rev Drug Discov 19, 311–332 (2020). https://doi.org/10.1038/s41573-019-0058-8

With the rise of new pathogens resistant to previous antibiotics, the need for new therapies and treatments is prevalent. One such therapy researchers are looking into is the cationic host defense peptide, abbreviated as CHDP. Peptides are strings of amino acids, which are the building blocks of protein. The CHDP peptides are found in a variety of organisms, including plants, invertebrae, amphibians, and even mammals. They are generally a smaller variety of peptides, containing 50 or fewer amino acids in total.

While originally noted for their direct microbicidal properties (ability to kill living microbes), past research demonstrated that they were relatively ineffective under certain physiological conditions. These conditions were often ones found in host cells: salt concentrations and the presence of DNA and other macromolecules (carbohydrates, lipids, proteins, nucleic acids). Further research has shown that these CHDP peptides exhibit a wider range of abilities past microbicidal properties.

One such ability is antibacterial activity. The CHDP targets the bacterial membranes, which are negatively charged. Since the CHDP contains cationic compounds (positively charged), it is attracted to the negatively charged bacterial membranes. This allows it to bind to the inner membrane of the bacteria, creating damage that leads to leakage of cell contents of the bacteria and subsequent cell death.

Another such ability is affecting cell wall synthesis. Some CHDP such as HNP1 or HBD3 are able to bind onto a compound called lipid II, which is required in the creation of peptidoglycan. Peptidoglycan is crucial in the creation of bacterial cell walls as it allows the cell to maintain its shape and prevents it from rupturing. When CHDP is applied to infectious bacteria, it blocks the lipid II from creating the peptidoglycan and consequently, the bacteria cell is not able to create its cell walls. That can be devastating for the bacteria as without a cell wall, it not only cannot maintain its structure, but it also cannot protect itself from responses from the host’s immune system.

Past antibiotic capabilities, CHDP also holds potential for antiviral treatment. CHDP has been effective in combating enveloped viruses through the destabilization of the envelopes during contact. These envelopes are the outermost layer of a virus, in charge of protecting the genetic material of the virus as it travels from host to host. However, they are also able to fight non-enveloped viruses by binding to the virus’s capsid (protein shells that enable viruses to enter the host cell) and preventing entry into the host cell’s nucleus. Since antibiotics do not work against viruses, the possibility of a new effective treatment of viruses is a significant development. Some viruses that CHDP have been shown to work against are the Zika virus, influenza, respiratory syncytial viruses, the vaccinia virus, and Kaposi’s sarcoma-associated herpesvirus.

CHDP also plays a role in antifungal treatment. Fungal species like Aspergillus fumigatus, Cryptococcus neoformans, Candida albicans, and Histoplasma capsulatum lead to 1.5 million deaths worldwide every single year. Unfortunately, very limited treatment options are available. However, CHDP offers hope as it has a variety of antifungal capabilities. It can hinder the function of mitochondria in fungi, preventing the fungi from generating sufficient energy to stay alive. It can also alter membranes, preventing the fungi from maintaining structure and staying protected from external threats. However, limitations for CHDP as antifungals exist because fungal biofilms are very resilient to treatment. Biofilms are structures of microorganisms sticking to a surface and to each other. There is still a need for research to be done on countering fungal biofilms.

Overall, cationic host defense peptides (CHDP) are a promising solution to many pathogens plaguing the world today. CHDP are able to both kill infectious pathogens as well as reduce inflammation caused by infections, making it an effective treatment against the disease. Unfortunately, current clinical trials have been a hit or miss. Although proven to be safe for long-term usage, many CHDP treatment clinical trials have ended because they could not be proven more effective than current treatments. Only some CHDP treatments are available on the market, such as topical treatments for oral disease and intravenous (administered through the veins) treatment of acute skin infections. However, as more clinical research is done on these molecules, more and more of their capabilities will be discovered.

Summarised by Jeannine Yu

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Works Cited:

American Society for Microbiology. https://journals.asm.org/doi/10.1128/mBio.02155-21. 

Strahl H Errington. “Bacterial Membranes: Structure, Domains, and Function.” Annual Review of Microbiology, U.S. National Library of Medicine, https://pubmed.ncbi.nlm.nih.gov/28697671/. 

“Lysis.” Lysis – an Overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/lysis. 

“Peptidoglycan.” Peptidoglycan – an Overview | ScienceDirect Topics, https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/peptidoglycan. 

“The Protein Capsid.” Encyclopædia Britannica, Encyclopædia Britannica, Inc., https://www.britannica.com/science/virus/The-protein-capsid.