The metal matters

Life on earth is carbon-based, but carbon-based life is impossible without metals. All living organisms, without exception, need metals to live. And so, all organisms must carefully manage their metal nutrition. They must find and take up enough metals, store metals if necessary, and apportion metals correctly to different organs, cells, organelles, and finally to specific proteins and enzymes. And, to avoid having too much of a good thing, all living organisms must also dispose of any surplus metal.

The question is how?

I have devoted my academic career to studying one metal, namely copper. Like the more familiar metals zinc and iron, copper is a vital nutrient but, unlike zinc and iron, copper is perhaps most notorious for being toxic. Too much copper kills and this is especially true for bacterial organisms. Humans have known about and subsequently exploited the antibacterial power of copper for millenia. Throughout ancient and modern history, we have used copper in various forms (solid metals, alloys, ionic salts, even nanoparticles) to combat bacterial infections (1). We now have more effective, copper-free antibiotics as human therapeutics, but until the late 1900’s, farmers still used copper-based compounds to prevent diseases in crops and animals.

Unfortunately, the prolonged use of copper had left a permanent legacy. Some bacteria in the environment have now evolved to become hyper-resistant to copper – they continue to survive and proliferate even when copper levels are 100 times higher than levels that kill most other living organisms.

As a PhD student in 2005, I wanted to know how. How do bacteria survive toxic levels of copper?

When there’s too much of a good thing.

At the time, work by leading scientists in copper biology had already shown that all bacteria have an innate ability to manage their copper status (2). This system for copper homeostasis works like this: a protein detects copper levels inside the bacterial cytoplasm and, if there is too much copper, an export pump quickly expels the surplus out to the periplasm or the extracellular space. Quite an elegant system. Over the next few years, our research group in Melbourne (Australia), along with many others around the world, found that the copper-resistant bacteria excel at handling toxic levels of copper because they have more – more sensors, more pumps, and, the coolest thing, sponges that can quite literally “mop up” the extra copper.

The year I graduated and embarked on my post-doctoral research, 2009, was an exciting year for copper biology. This year, scientists discovered that the animal and human immune system can also use copper to kill bacteria – not copper from drugs, but instead copper that is naturally circulating in the body (3)!

Many international research groups, including ours in Brisbane (Australia), soon built on this discovery and showed that if we damaged the copper sensor or pump from an infectious bacterial species by mutation, the organism almost always became less infectious – they only caused mild diseases or not at all, at least in experimental animal models (4).

But why? Why do bacteria need to remove excess copper? Or, put differently, why does copper kill bacteria?

Another breakthrough study in 2009 suggested that the extra copper in bacteria goes where it does not belong (5). Remember that bacteria, like all living organisms, must apportion each and every metal correctly to different proteins and enzymes within the bacterial cell. Surplus copper can become accidentally allocated to enzymes that do not need and, in most cases, cannot use copper. Our research group in Brisbane, along with many other international scientists, have now found many examples of bacterial proteins that become poisoned by too much copper. This poisoning usually inactivates the enzymes and subsequently causes the bacteria to stop growing and eventually die.

How is this knowledge useful in the real world?

We are hoping to apply this knowledge into new ways to combat infectious diseases. Many bacterial infections have now become untreatable, even by the most powerful last-resort antibiotics. Scientists are racing to find new and more effective drugs. But, as Nobel Laureate Sir James Black said, the best way to discover a new drug is to start with an existing drug. Remember, humans have already developed (and used) copper-based antibiotics for thousands of years, albeit for use mostly in plants and animals. Many researchers like my new team in Durham (UK) are now working to modernise these ancient copper drugs and develop them as human therapeutics (6). Of course, it has not escaped our attention that even our own immune system can use naturally circulating copper to kill bacteria. We are also looking for ways to boost this immune action of copper.

When there’s just enough metals.

Now that I am an Assistant Professor and group leader at Durham University, I have become interested in why bacteria need copper as a nutrient. Even the most basic processes in bacteria, like respiration and the production of energy, cannot occur without copper (7). Yet, this aspect of copper biology has been somewhat overshadowed by the acute toxicity of this metal. Scientists have focused most of our attention on how bacteria move copper out but have rarely asked the question how they get copper in.

How do bacteria get enough, or get any, copper in the first place? How do they apportion and store copper correctly within the cell?

These fundamental questions in copper biology have important implications for health and diseases. Can infectious bacteria utilise the copper that is circulating in the body of the infected human host? Instead of becoming poisoned, can bacteria use this copper to promote their own growth and survival, and thus cause a more severe infection? These scenarios are all plausible but how and where does biology draw the line? How much is too little copper and how much is too much?

Together with collaborators in Newcastle (UK) and Brisbane (Australia), we hope to be able to tease out the answers in a few years. So, stay tuned!

© Karrera Djoko

References:

1. H. H. A. Dollwet and J. R. J. Sorenson, Historic uses of copper-compounds in medicine, Trace Elements in Medicine, 1985, 2, 80-87.
2. C. Rensing and G. Grass, Escherichia coli mechanisms of copper homeostasis in a changing environment, FEMS Microbiology Reviews, 2003, 27, 197-213.
3. C. White, J. Lee, T. Kambe, K. Fritsche and M. J. Petris, A role for the atp7a copper-transporting atpase in macrophage bactericidal activity, Journal of Biological Chemistry, 2009, 284, 33949-33956.
4. K. Y. Djoko, C. L. Ong, M. J. Walker and A. G. McEwan, The role of copper and zinc toxicity in innate immune defense against bacterial pathogens, J Biol Chem, 2015, 290, 18954-18961.
5. L. Macomber and J. A. Imlay, The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity, Proceedings of the National Academy of Sciences of the United States of America, 2009, 106, 8344-8349.
6. M. E. Helsel and K. J. Franz, Pharmacological activity of metal binding agents that alter copper bioavailability, Dalton Transactions, 2015, DOI: 10.1039/c5dt00634a.
7. L. J. Stewart, D. Thaqi, B. Kobe, A. G. McEwan, K. J. Waldron and K. Y. Djoko, Handling of nutrient copper in the bacterial envelope, Metallomics, 2018, DOI: 10.1039/c8mt00218e.

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