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Could the properties of metals and animal peptides be harnessed to reduce infection and antimicrobial resistance?

Simran Patel is a second year biological sciences student at Imperial College London, London, UK.

Mebruka Mohammed is a medical writer at St Giles Medical, London, UK.

Franziska Paratore-König is a sociologist at St Giles Medical, Berlin, Germany.

Steven Walker is the director at St Giles Medical, London, UK and Berlin, Germany.

Antimicrobial resistance (AMR) is developing rapidly and threatens to outstrip the rate at which new anti-infective agents are introduced.1 The emergence and spread of multi-drug- and pan-drug-resistant organisms is increasingly causing fatal infections.2 AMR not only affects human and animal health, notably among the elderly and immunocompromised, but it also poses a major socioeconomic risk.3

A review on the global crisis of AMR, chaired by Jim O’Neill, estimated that about 700 000 lives are lost worldwide annually due to antimicrobial-resistant infections.4 Reflecting on this, Laura JV Piddock noted that the societal and financial cost of not tackling the AMR crisis will be $100 trillion by 2050.5 Other studies estimated that unless effective agents become available, there would be between 11 million and 444 million excess deaths, and the global economy would shrink by between 0.1% and 3.1% by 2050.6

As a result of increasing AMR, scientists are turning to natural compounds in the hope of finding new antibacterial treatments.7 These compounds have often been used in traditional medicine worldwide for centuries. The complexity of many natural extracts means that multiple bacterial structures and metabolic pathways are targeted simultaneously. This reduces the risk of developing resistance compared to an agent with one primary mode of action.7 Many articles have now been published, often with the help of indigenous communities, demonstrating that some natural remedies are more than just old wives’ tales.8 Here we examine some of the leading contenders.

Inorganic materials for antimicrobial use: metals and clay

“… scientists are turning to natural compounds in the hope of finding new antibacterial treatments.”

Metals in various forms have been used since ancient times to treat infections, including copper, zinc, and silver. These inorganic materials have been shown to kill or inhibit the growth of microbes via a range of diverse mechanisms.9 Therefore, metals have recently found applications in advanced antimicrobials to reduce the development of resistance.10

Copper

The antimicrobial benefits of copper were known in Ancient Greece, India, and Egypt, where potentially contaminated drinking water was stored in copper vessels.11 Nowadays, copper is sometimes used to coat exposed surfaces to reduce the spread of infection. In a medical setting, this may include bed rails and door knobs.12 To prevent pathogenic biofilms growing on the surface of implants, they are sometimes copper-coated or made from a copper alloy.12 A historical example of the latter is the 2300-year-old bronze prosthetic ‘Capua leg’ found at a Roman burial site.11

While the potential benefits of copper have long been recognised, its antimicrobial chemistry has only more recently been elucidated. By disrupting the electrical potential across bacterial cell membranes, copper ions cause the membranes to become more permeable.12 Copper also generates damaging reactive oxygen species by catalysing amino acid oxidation and the Fenton reaction.12

Zinc

The effects of zinc and copper are closely related to the pathogen-killing mechanism in Eukaryotes, where oxidative stress is used to kill invading microbes.10 In the 1st century C.E., the Greek physician, Dioscorides, described the oxidation process of zinc in his writing, ‘De Materia Medica’. An even earlier reference to the potential value of this metal was found in an Indian document, The ‘Charaka Samhita’, which dates from 500 B.C.E. The text describes a healing salve called ‘pushpanjan’, which was used to treat eye infections and open wounds.13 In modern medicine, zinc is an essential trace element that plays a significant role in wound management. Topical application of zinc oxide promotes wound healing by enhancing autodebridement and epithelialisation while simultaneously decreasing inflammation and bacterial growth.14

“… Kisameet clay … could complement our dwindling arsenal of treatments.”

Silver

Contact with silver is another example of a metal causing bacterial oxidative stress. Further, its positive ions can destabilise the negatively-charged cell membrane and nucleic acids.15 People have drank water out of silver vessels for centuries, possibly since the time of Alexander the Great.11

Today, the focus of silver’s medicinal applications is on ions and nanoparticles, such as embedding silver in wound-dressing material.12 Toxicity can be an issue, because there is no skin to act as an innate immune barrier in the case of wounds. Therefore, the concentration of silver in the dressing needs to be maintained below a safe level.15

Silicon dioxide

Recently, the potent antibacterial activity of clay minerals has generated scientific interest. One example is Kisameet clay (KC), consisting of crystalline sheets of silicon dioxide found in glacial deposits on the central coast of British Columbia, Canada.16 Here, the indigenous Heiltsuk First Nation people have used KC therapeutically for generations.17

The clay contains bacteria, notably Actinobacteria, which produce antimicrobial chemicals. When six Gram-positive and Gram-negative multidrug-resistant strains of common bacteria (commonly referred by the acronym ESKAPE pathogens) were incubated with KC, viable organisms could no longer be identified after 2 days of contact.16 With conventional antibiotics, a high level of antibiotic resistance involving multiple adaptive mechanisms would normally have been anticipated.18 These encouraging results suggest that KC, or variations thereof, could complement our dwindling arsenal of treatments.16

Organic materials for antimicrobial use: animal-derived antimicrobial peptides

Antimicrobial peptides (AMPs) are naturally occurring macromolecules made of amino acids that play a crucial role in host innate immunity.19 They are of increasing interest because of their broad-spectrum antimicrobial activity, rapid killing powers, limited toxicity, and cell selectivity.20 Since their discovery in 1939, more than 2000 AMPs have now been identified from animals, fungi, plants, and bacteria.21 AMPs exert antibacterial activity by causing membrane permeation or perforation, thereby inducing leakage of intracellular contents. Alternatively, they may enter the organism causing a range of toxic effects.19

Application of AMPs

“Antimicrobial peptides from across the animal kingdom kill pathogens in different ways.”

The potential uses of AMPs are as diverse as their sources. Extracts from Tenebrio molitor mealworms have, for example, been found to have an inhibitory activity against bacteria often associated with food-poisoning, such as Escherichia coli, Bacillus cereus, and Staphylococcus aureus. Similarly, they are active against the harmful fungi Aspergillus flavus, Aspergillus parasiticus, and Pichia anomala.22 One practical application could be as a safe natural preservative inhibiting bacterial growth, thereby prolonging the shelf life of a range of foods.22

Recombinant technology can be used to produce and purify the genes retrieved from potential valuable AMPs. Once their structure is identified, AMPs can be designed as semi-synthetic or totally synthetic constructs for potential clinical use.23 Wang et al experimented on newly identified AMPs isolated from the lungs and bone marrow of Chinese painted quails (Coturnix chinensis). Research showed that both the synthetic and the semi-synthetic derivatives of the quail AMPs exhibited strong bactericidal properties against 11 strains of Gram-positive and Gram-negative bacteria.24

AMP mechanisms of action

AMPs from across the animal kingdom kill pathogens in different ways. For example, lycotoxins are found in the venom of the spider Lycosa carolinesis. These AMPs can create pores in bacterial cell membranes, which kill the invader by releasing its internal contents.25 Similarly, androctonin in haemolymph from the scorpion Androctonus australis, and melittin in venom from the bee Apis mellifera, work by making the bacterial cell membrane more permeable.25

Snake venom also contains AMPs, which explains why snake bites do not generally become infected.25 The venom contains the oxidation enzymes L-amino acid oxidase and phospholipase A2, which induce oxidative stress25 rather like metals do. These new discoveries add to other traditional remedies being rediscovered, such as the use of honey and medicinal maggots for the treatment of necrotic and infected wounds.

Conclusion

The inappropriate and excess use of antibiotics has resulted in an AMR crisis. People are increasingly dying because current drugs are no longer effective. New anti-infective agents cannot be developed fast enough, and when they are, they are soon out of date. This makes the huge cost and return on new drug discovery unattractive for major pharmaceutical companies.

The application of traditional remedies and the discovery of novel antibacterial molecules may help solve the current antibiotic crisis. Recent advances in extraction and isolation techniques, and in state-of-the-art technologies involved in organic synthesis and chemical structure elucidation, have accelerated the numbers of antimicrobial molecules originating from natural sources.26 In the last 6 years, more than 250 antibacterial compounds have been isolated from natural sources. In addition to their therapeutic use, antimicrobials from natural sources show potential for use as food preservatives to increase shelf life and to prevent food-borne diseases.27

As AMR continues to spread, the importance of nature in providing future generations of medicines and sterile surfaces cannot be underestimated. These will likely serve as rich sources of chemically diverse and biologically active compounds in the ongoing search for novel antimicrobials.

References
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22. Hwang D, Lee SH, Goo T-W, Yun E-Y. Potential of antimicrobial peptide-overexpressed Tenebrio molitor larvae extract as a natural preservative for Korean traditional sauces. Insects 2022; 13(4): 381.
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Featured photo by rhoda alex on Unsplash.

The BJGP is the world-leading primary care journal. At BJGP Life we add multi-media comment and opinion for the primary care community.

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