An ancient alternative to antibiotics: Clays

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The use of clays in medicine is a practice developed in ancient times, recorded in antiquity (Aristotle; 4th century BC), and the health benefits have been documented on all continents [1]. But few in the field of infectious disease research think seriously about why natural minerals were used, other than as a pre-historic Band-Aid or digestive [2].

I’m a geologist, but I grew up in a family of physicians and was acquainted with the fascinating pictures of diseases in medical textbooks. I never was fond of bacterial biofilms (slime), but somehow I was drawn to playing in the mud. Professionally, I ended up studying clays, which mixed with water makes mud (also slime), called a poultice when used in medical applications. The chemistry of particular clays, when hydrated, is key to their antibacterial properties.

Clays are microscopic minerals (<2µm) that comprise sediments. Because of their small particle size and layered structure, one group of clay minerals, called smectites, have a surface area up to 700 m2/g [3]! That’s an enormous mineral surface in contact with water; just 7g of this clay could cover a football field in a monolayer, creating an immense chemical factory.

Evidence for antibacterial clay

My research into the antibacterial properties of clays began over a decade ago when Line Brunet de Courssou, a French philanthropist, working in the Cote D’Ivoire, Africa, sent a message to the Clay Minerals Society listserv. She was treating patients suffering from Buruli ulcer, a necrotizing fasciitis caused by Mycobacterium ulcerans. By applying a poultice of ‘French Green Clay’ daily, she had cured over 100 people, mostly women and children (the food gatherers). At that time there was no antibiotic cure for this infection: only excision or amputation. She went to the World Health Organization [4] and requested funds to help in cheaply treating these impoverished communities with clay. Of course they could not fund her, but suggested that scientific studies must be done to understand the healing mechanism.

The first message she posted returned no response. No one in the Clay Minerals Society knew anything about Buruli ulcer – that sounded like microbiology! Six months later, in exasperation, Line’s son posted, “I guess no Clay Scientists care about poor people suffering in Africa”.

Well, here’s the problem. As scientists, we’re so specialized, that no one has time to think about problems so far out of their field!  Or if they do, how does that get funded? But guilted, I wrote back and said that I knew nothing about treating infections with clay, but if they would send me the clay they used, I could look at it in an electron microscope and with X-ray diffraction I could tell them what kind of minerals were in it.

“You can’t take these people seriously! You’ll be labeled a quack!” warned my family of physicians, “Are you crazy? What do you know about infectious diseases?” I only knew that they had photographic documentation of healing this horrible infection with clay. This is an observation and as a scientist it is our nature (our job) to investigate, form a hypothesis and begin testing it – surely there was something we might learn about how nature fights pathogens.

Naïvety can take you to parts unknown. The National Institutes of Health (NIH) is an unlikely territory for a geologist, but I decided to drop in to the NIH Center for Complementary and Alternative Medicine in Washington, DC (USA) and meet the Program Director, a microbiologist. I had a 15-minute ‘show and tell’, and was armed with some preliminary data showing that the antibacterial clay used to heal Buruli ulcer contained reduced Fe and had a remarkably large surface area – “the crystals are 200nm in diameter!” And that was it. The Director was hooked – “I didn’t know clays were crystals!” So what is the chemical interaction that makes these nano-crystals antibacterial?

Interdisciplinary Communication

Exploratory research funds in hand, the first roadblock was a lingo problem. Minerals, to a physician are elements (Na, K, Ca, etc.). But minerals to a geologist are inorganic compounds having a characteristic chemical composition and repeating atomic structure, which is expressed in its crystalline form [5]. This is important because it is the mineralogical structure of these clays that provides the ‘chemical factory’ responsible for the antibacterial mechanism [6].

Imagine a clay mineral (specifically a reduced Fe-bearing smectite), as a peanut butter & jelly sandwich. The silicate framework makes layers of repeating sheets of tetrahedral (T) and octahedral (O) metal–oxygen bonds (e.g., Si-O, Al-O, Fe-O): the essential ‘bread’ of the structure. In between T-O-T layers there are interlayer cations and water. The cations, attracted to the negatively-charged silicate surface, stick to the bread like a layer of peanut butter. The more loosely held ions form a hydrated second layer, like a jelly. This jelly layer becomes slippery with water added as the silicate layers slide around. You slide down in the garden on this smectite-type clay.

That region between the bread, the interlayer, is important to the antibacterial action because there, any soluble Fe2+ from the clay is protected from oxidation, and like a ‘tiny time capsule’, this active ingredient is slowly released to solution where it interacts with the bacteria. It is the oxidation of the released Fe2+ to Fe3+ that damages bacterial membranes and intracellular proteins [6]. We know this because just adding FeCl2 to a solution might kill bacteria for a short time, but it oxidizes so quickly it is ineffective long-term. The slow release of large amounts of Fe2+ is what effectively kills even the most troublesome antibiotic-resistant pathogens, like methicillin-resistant Staphylococcus aureus.

An Alternative Antibacterial Mechanism

If you take the antibacterial clay out of the ground where it is in a low oxidation state and add water, that reduced Fe2+ (blue-green in color) becomes oxidized Fe3+ (rust red). The transfer of electrons during oxidation is central to the antibacterial reactions. First the Fe2+ is dissolved, and becomes available to bacteria for energy. Like a ‘Trojan horse’, it easily passes through the outer and inner membranes of a broad-spectrum of Gram-negative, Gram-positive and Mycobacterial species tested [7]. Well-known Fenton reactions have been demonstrated to damage organic molecules [8], but pathogenic bacteria that live in an oxidizing world are used to that, having developed a variety of genetic defenses against reactive oxygen species [9]. Why then is it possible for so much Fe2+ to enter the inner sanctum of these pathogens, including antibiotic resistant strains [10], where its final intracellular oxidation indiscriminately destroys proteins and DNA [6,11]?

Recent studies [12,13] support the mechanism determined from our investigations of natural antibacterial clays [6,14,15]. Wang et al. [13] further show that chemical reduction of an Fe-bearing smectite, after it has oxidized during treatment of a pathogen, allows the mineral to be re-used. This is an exciting development that could lead to the sustainable use of clays in wound care.

Implementation of Alternative Antibacterials

At a recent Bio-interfaces Symposium (September 21–23, 2015, AZ, USA), a medical researcher commented on our study of antibacterial clays, stating that it was, “A fascinating study that would never see the light of day…because no one can make money from it,” as clays are natural materials, and therefore not patentable. There are obvious risks involved in using natural mineral cures. Some deposits may contain toxins (As, Hg, Pb), the effect on epithelial cells may vary, and the costs of quality control could be burdensome. However, if we are serious about pursuit of alternatives to antibiotics, we cannot accept this avaricious attitude. The rational use of these inexpensive resources with proven effectiveness in killing antibiotic-resistant pathogens still needs to be tested, but could be easily implemented for antibiotic-free animal feedstock, agricultural pathogens and production of antibacterial building materials.

Moreover, the development of new synthetic materials, using the properties exhibited by natural clays but with controlled chemical compositions, could lead to applications in wound care and coatings for medical implants. Many different bacterial defenses are defeated by the antibacterial clays, which may challenge the bacterial development of resistance genes. The most difficult challenge now is communicating this trans-disciplinary thinking ‘out of the box.’ This research requires concerted effort to communicate across tough disciplinary boundaries. If a geologist cannot communicate with a microbiologist, then we may miss this golden opportunity to implement a proven alternative to antibiotics.

Acknowledgements

The opinions expressed are experiential, but the research was funded by grants from the National Institutes of Health (NCCAM: R21 AT003618) and National Science Foundation (GEO-EAR 1123931 and GEO-EAR 1719325).

References
  1. Laufer B. Geophagy. Field Museum of Natural History, Chicago, USA, Publication 280, 198 (1930).
  2. Williams LB, Haydel SE & Ferrell RE. Bentonites, Bandaids and Borborygmi. Elements, an International Magazine of Mineralogy, Geochemistry and Petrology. Derek Bain (Ed.) 5(2) 99–102 (2009).
  3.  Srodon J & McCarty DK. Surface area and layer charge of smectite from CEC and EGME/H2O-retention measurements. Clays and Clay Minerals, 56(2) 155–174 (2008).
  4. Brunet de Courssou L. 5th WHO Advisory Group Meeting on Buruli Ulcer, Study Group Report on Buruli Ulcer Treatment with Clay. Geneva, Switzerland, March 14 (2002).
  5. Klein C & Hurlbut CS Jr. Manual of Mineralogy (after James D. Dana) (21st edition), John Wiley and Sons Inc, NJ, USA. 681 (1993).
  6. Morrison KD, Misra R & Williams LB. Unearthing the Antibacterial Mechanism of Medicinal Clay: A Geochemical Approach to Combating Antibiotic Resistance. Sci. Rep. 5, 19043, doi:10.1038/srep19043 (2016).
  7.  [7] Haydel SE Remenih CM & Williams LB. Broad-spectrum in vitro antibacterial activities of clay minerals against antibiotic-susceptible and antibiotic-resistant bacterial pathogens. J. Antimicrob. Chemo. 61, 353–361 (2008).
  8. Lemire JA, Harrison JJ & Turner RJ. Antimicrobial activity of metals: mechanisms, molecular targets and applications. Nat. Rev. Microbiol. 11, 371–384 (2013).
  9. Imlay JA. Transcription factors that defend bacteria against reactive oxygen species. Annual Rev. Microbiol. 69, 93–108 (2015).
  10. Hohle TH, Franck WL, Stacey G & O’Brian MR. Bacterial outer membrane channel for divalent metal ion acquisition. Proc. Natl Acad. Sci. USA. 108, 15390–15395 (2011).
  11. Keyer K & Imlay JA. Superoxide accelerates DNA damage by elevating free-iron levels. Proc. Natl Acad. Sci. USA. 93, 13635–13640 (1996).
  12. Tran N, Mir A, Mallik D, Sinha A, Nayar S, Webster TJ. Bactericidal effect of iron oxide nanoparticles on Staphylococcus aureus. Int. J. Nanomedicine. 5, 277–83 (2010).
  13. Wang X, Dong H, Zeng Q, Xia Q, Zhang L, Zhou Z. Reduced iron-containing clay minerals as antibacterial agents. Env. Sci. Tech., 51, 7639–7647 (2017).
  14.  Londoño SC, Hartnett H & Williams LB. The antibacterial activity of aluminum in clay from the Colombian Amazon, Env. Sci. Tech. 51, 2401–2408 (2017).
  15. Williams LB, Metge DW, Eberl DD, Harvey RW, Turner AG, Prapaipong P, Poret-Peterson AT. What makes natural clays antibacterial? Env. Sci. Tech., 45, 3768–3773 (2011).
Author affiliations

Lynda B. Williams, Ph.D. 1

1 Research Professor, School of Earth & Space Exploration, Arizona State University, 550 E. Tyler Mall, Physical Sciences F-686, Tempe, AZ 85287-1404 USA

lynda.williams@asu.edu

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