By Wang Guo
Pathogenic microbes and cancer cells evolve due to natural selection caused by interactions with the immune system. Therefore, researchers and pharmaceutical companies must be constantly innovating and developing new drugs to fight existing diseases, but also newly emerging ones. However, creating a new drug from scratch is an extremely arduous, time-consuming and risky venture. Instead, scientists should look more into chemical compounds with potential therapeutic properties found in, for example, amphibians. Apart from complying with an essential middle position in the food chain, many amphibians secrete toxic chemical compounds that, once extracted and purified, were demonstrated to potentially kill microbes and even cancer cells. Unfortunately, amphibians are at extreme risk of extinction due to habitat destruction, climate change and diseases. Indeed, around one-third of amphibians are disappearing worldwide.1
The continuous usage of antibiotics can cause bacteria and fungi to develop resistant mechanisms against them. Some strains even develop resistance to multiple different antibiotics, being a serious problem for public health. An infamous example IS methicillin-resistant Staphylococcus aureus (MRSA) because MRSA is resistant to many common antibiotics.2 Xenopus, a genus of African frogs, secrete antimicrobial peptides that seem promising for revolutionising the fight against pathogenic bacteria and fungi. In particular, the peptide PGLa-AM1 extracted from Xenopus amieti was shown to be effective against both Escherichia coli and Staphylococcus aureus at the same time. Therefore, PGLa-AM1 is a broad-spectrum anti-bactericidal. This increases the cost-effectiveness of PGLa-AM1, which is essential for industrial production provided PGLa-AM1 is finally commercialised. Colistin is one of the most powerful antibiotics we currently have and is used very sparely as a last resort to cure infections caused by multiple-drug-resistant bacteria. However, there are already some bacterial strains that demonstrate resistance to colistin. Exposure of colistin-resistant strains of Acinetobacter baumannii to PGLa-AM1 has been shown to inhibit bacterial growth. Furthermore, PGLa-AM1 was not harmful to human erythrocytes.3 The reason for this is that the frog Xenopus amieti secretes PGLa-AM1 to eliminate harmful bacteria from its skin, so PGLa-AM1 is specifically designed to act on prokaryotic cells. Our cells are eukaryotic, having huge differences both metabolically and structurally to prokaryotic cells, so PGLa-AM1 shows low levels of toxicity for humans.
Mammals, including humans, rely mainly on the adaptive immune system mediated by cells to fight against cancer cells. This has advantages like increasing precision, but, simultaneously, cytotoxic chemicals become obsolete, playing a secondary role in mammals. However, the adaptive immunity of amphibians is not that developed compared to mammals, so they rely more on the innate immune system using cytotoxic chemicals. Subsequently, these are perfected over millions of years of evolution to become extremely effective against cancer cells. Indeed, few of these molecules are exclusive to amphibians and similar molecules in mammals have not been found yet. For instance, Phyllomedusa hypochondrialis produce a unique peptide called tryptophyllin. Experiments revealed that tryptophyllin has inhibitory effects on the growth of human prostate cancer cells. Tryptophyllin seems also to inhibit bradykinin, which is a pro-inflammatory peptide linked to many cardiac diseases.4
However, there are several reasons why peptides secreted by amphibians have not reached the market and subsequent commercialisation. First, these defensive peptides are usually present in relatively high concentrations in amphibian bodies as they are the main mechanism of defence against diseases for amphibians. In humans, the concentration of defensive peptides is much lower.5 If we decrease the concentration up to a safe level, then we lose effectiveness on the way and vice versa. Because of this, many amphibian defensive peptides never progress further in the pharmaceutical industry. Second, there are already alternatives on the market that work the same and with better results, added to the plus that they are already well-studied and clinically tested. The fact that a defensive peptide forms a frog presents anti-cancer properties does not necessarily mean that is high enough with already established drugs. In most cancer, amphibian peptides lose against conventional properties. The interest that the pharmaceutical industry initially had in amphibian peptides has been lost and the only way to resurrect the interest would be to find applications of amphibian peptides that no conventional drug could have.
This last possibility can realistically become true provided R&D is done because there are around 7144 amphibian species worldwide,6 each one with hundreds of different peptides that need to be characterised. There is a high possibility of finding the next ‘colistin’ in amphibians because we have only studied a small number of amphibian species. However, another sad reality emerges. Amphibians are sensitive to environmental changes. Factors like pollution or habitat destruction are reducing dramatically their populations worldwide. Current conservation activities are not good enough to preserve the species. If we continue like this, amphibians will disappear, which is already an ecological disaster, but the loss of amphibians will mean they take their pharmacological secrets with them…never to come back.
References
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2. Wright H, Bonomo RA, Paterson DL. New agents for the treatment of infections with Gram-negative bacteria: restoring the miracle or false dawn? Clin Microbiol Infect. 2017 Oct;23(10):704–12.
3. Conlon, J.M., Mechkarska, M., 2014. Host-defense peptides with therapeutic potential from skin secretions of frogs from the family pipidae. Pharmaceuticals (Basel) 7, 58–77. https://doi.org/10.3390/ph7010058
4. Conlon JM, Mechkarska M, Leprince J. Peptidomic analysis in the discovery of therapeutically valuable peptides in amphibian skin secretions. Expert Review of Proteomics. 2019 Dec 2;16(11–12):897–908.
5. Wang R, Lin Y, Chen T, Zhou M, Wang L, Shaw C. Molecular cloning of a novel tryptophyllin peptide from the skin of the orange-legged monkey frog, Phyllomedusa hypochondrialis. Chem Biol Drug Des. 2014 Jun;83(6):731–40.
6. Bevins CL, Zasloff M. Peptides from frog skin. Annu Rev Biochem. 1990;59:395–414.
7. Amphibian Species of the World [Internet]. [cited 2022 Jun 10]. Available from: https://amphibiansoftheworld.amnh.org/
Article written in June, 2022
Imperial Bioscience Review 