Death by a thousand cuts: how antibacterial clays kill

OMT blue clay
A section of blue clay from the open pit mine at the Oregon Mineral Technologies clay deposit near Crater Lake. The antibacterial blue clay is surrounded by white clay which lacks antibacterial properties. (Credit: Keith Morrison)

By now most of you will have heard that more and more bacteria are becoming impervious to the many life-saving antibiotics on which we’ve come to rely. In November, scientists in China sampling bacteria from meat and hospitalized patients found a new gene called MCR-1 that confers resistance to colistin, a drug that is currently used as a last resort when all other antibiotics have failed. This report was the latest in a series of increasingly worrisome news that have spurred researchers to look for new ways to combat antimicrobial resistance. While some scientists are exploring futuristic ideas like light-activated nanoparticles, others are looking to nature and literally digging up dirt for inspiration.

In a paper published recently in Scientific Reports, researchers have revealed for the first time the mechanism behind the antibacterial properties of medicinal clay.

“People have been eating clays for thousands of years,” says Dr. Keith Morrison, the report’s lead author and now a postdoctoral fellow at the Lawrence Livermore National Laboratory. The purported benefits of eating clay relate to its ability to grab heavy metals and other “toxins” and expel them from your body. However, the scientific evidence supporting this idea (and the idea that our bodies need any detoxing at all) is lacking.

As a PhD student at Arizona State University, Morrison was interested in another curious property of some medicinal clays—their ability to kill bacteria. While the use of clay to treat wounds and skin infections can be traced back to the 19th century, the scientific study of these antibacterial clays is a fairly new field.

Dr. Lynda Williams was Morrison’s PhD supervisor and one of the first people to apply the rigours of scientific testing to antibacterial clays. In a 2008 paper, Williams and her team tested the antibacterial activities of two types of French green clay against a diverse group of bacterial pathogens. Despite the fact that both clay minerals had been used to treat Buruli ulcers, a flesh eating disease caused by the bacteria Mycobacterium ulcerans, only one type of clay was able to kill bacteria in the lab. “Lynda’s lab was the only lab out there doing anything like this,” says Morrison. “I saw it and immediately knew that’s what I wanted to work on.”

Their study of the French green clays prompted them to look for other deposits of antibacterial clays. In the clay deposits near Crater Lake in the Cascade Mountains of Oregon, they struck pay dirt. In a 2014 paper, Morrison and Williams showed that the blue clays in the deposit, which is an estimated 20 to 30 million years old, effectively killed cultures of Escherichia coli and Staphylococcus epidermidis. Further testing showed that the clays were also 100% effective in killing other human pathogens including antibiotic resistant bacteria like methicillin resistant Staphylococcus aureus (MRSA).

Morrison
Biogeochemist Dr. Keith Morrison mapping antibacterial clay zones exposed by creek drainage. (Credit: Keith Morrison)

Building on that paper, the researchers next asked how the clays were killing the bacteria. “We knew that [the clays] were releasing iron and aluminum [and] we knew the cells were taking up some of the iron,” says Morrison. “Our objective was to try and figure out a more mechanistic understanding of how the bacteria are being killed.”

Once released, iron and aluminum stick to and damage the bacteria’s outer layer, a protective coating made of fats and proteins, causing the proteins to misfold into improper shapes. “The cell has to really respond to that [damage] and breakdown those these misfolded proteins and remove them from the cell wall so the cell can function properly,” says Morrison. “As this is happening, you have only [iron] entering the cell.”

Iron is an essential nutrient for bacteria and one that they are constantly scavenging from their environment. But iron can also react with hydrogen peroxide to generate what are known as hydroxyl radicals. These compounds are similar to reactive oxygen species in that they can damage just about anything inside a cell—proteins, DNA and fats. “The cells get greedy and take up as much iron as they can if it is available,” says Morrison. As they become overloaded with iron, more hydroxyl radicals are produced leading to extensive DNA and protein damage.

Morrison believes that it is this dual assault on the bacteria’s outer coating and internal machinery that ultimately leads to cell death. “You kind of have multiple cellular processes just being bombarded all at once,” he says. An attack of this magnitude is likely to overwhelm the cell’s antioxidant defense mechanisms, leaving the bacteria unable to cope with the stress.

Such a strategy also sets antibacterial clays apart from traditional antibiotics on the market, which usually target a single cellular process—for example, DNA replication or cell wall construction. This difference could mean a lower likelihood of bacteria becoming resistant to antibacterial clays. “We would argue that it would be much more challenging for them to establish resistance…because we’re damaging multiple cellular systems,’” says Morrison. “It’s just too many variables for [the bacteria] to overcome on a short timescale.”

While iron and aluminum seem to be the key components in these clays, other properties are contribute to its long-lasting antibacterial effects. When the researchers tested a solution of just iron and aluminum dissolved in the same concentrations as was released from the clay, they did not see the same sustained killing as the original clay compounds. Further, the two metals were synergistic—the combined effect of iron and aluminum was greater than that of either metal alone.

Despite their promising results, Morrison is quick to point out antibacterial clays are still far from reaching the clinic. Thus far, the researchers have only completed in-depth studies of the French green clays and Oregon blue clays but they believe that similar antibacterial clay deposits are common and widespread around the world. A key question that remains is whether all antibacterial clays work in the same way. Figuring out how different types of clays work will provide valuable information that can guide the design of antibacterial mineral mixtures.

Reference:  Morrison KD, Misra R, & Williams LB (2016). Unearthing the Antibacterial Mechanism of Medicinal Clay: A Geochemical Approach to Combating Antibiotic Resistance. Scientific reports, 6 PMID: 26743034

 

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