Blocking bacteria's access to iron: an interview with Dr. Laxminarayana Devireddy

Dr. Laxminarayana DevireddyTHOUGHT LEADERS SERIES...insight from the world’s leading experts

Why do bacteria need iron?

Iron is a key nutrient for nearly all living organisms, including bacteria. Iron is a cofactor for many enzymes necessary for basic metabolic reactions such as DNA synthesis and electron transport. Iron serves as the conduit for the electron transport chain that generates the energy necessary to drive the bacterial cell.

The nutrient metal is involved in a wide assortment of critical processes in bacteria, affecting composition, intermediary and secondary metabolism, enzyme activity and other cellular interactions.

Bacteria greatly depend upon on an adequate iron supply so that they can solubilize and assimilate iron in order to grow. Because iron is so essential to the survival of bacteria, these microbes tap into multiple iron sources to secure their growth.

What are bacterial siderophores and how do they capture iron?

At an earlier stage in the planet’s history, all iron was available in soluble form because there was no oxygen in the atmosphere. Once oxygen started accumulating in the atmosphere, oxidized iron became unavailable to organisms because it precipitates at neutral pH in aqueous solutions.

Bacteria were able to use oxidized iron by secreting a small molecule siderophore to transform iron into a soluble form. Bacterial siderophores are small hydrophobic molecules hyperexcreted by bacteria in iron-limiting conditions.

There are more than 500 different types of siderophores.  The purpose of siderophores is to solubilize iron because oxidized iron is insoluble in water at neutral pH. 

Bacterial siderophores have an extraordinary affinity - irresistible attraction - to iron. The affinity of bacterial siderophore to iron is so great that it can strip the iron atom from carrier proteins such as transferrin in human plasma.

Anywhere there are small amounts of iron in the environment, bacteria can effectively capture the iron and solubilize it through siderophore.

Do humans possess siderophores?

Yes. Mammals have siderophore-like molecules whose main function is to ferry iron into mitochondria.

Mitochondria in our cells are highly similar to bacteria, and like bacteria, human mitochondria acquire iron to produce energy for our cells and use a siderophore mechanism to obtain it.

Essentially, mammalian mitochondria are membrane-encased subunits within cells that generate most of the cell’s energy, and like their bacteria counterparts, mammalian mitochondria have their own siderophore mechanism that seeks out, captures and delivers iron for utilization.

Are bacteria able to use the host’s iron-capture machinery?

Yes. Bacteria can acquire iron from their own siderophores as well as siderophores of humans. Because mammalian siderophore is so similar to bacterial siderophore, we know that bacteria can utilize the siderophore from both sources.

At the test tube level, we found that bacteria can feed on iron supplied by bacterial siderophore and mitochondrial siderophore. From this abundant supply of iron, bacteria proliferate to the point of making the host mammal very ill with an infection.

Please can you outline your recent research that studied mice deficient for mitochondrial siderophore?

Iron acquisition is critical for pathogenic bacteria. As mentioned above, bacteria can utilize siderophores of mammalian origin. If this hypothesis is true, then we would expect that mice lacking endogenous siderophore resist bacterial infection.

To test this hypothesis, we derived mice lacking the endogenous siderophore. We found that siderophore-deficient mice are resistant to bacterial infections. We also found that normal mice respond to infection by suppressing the synthesis of endogenous siderophore.

Were the mice deficient for mitochondrial siderophore able to resist infection by E. Coli altogether?

Yes. Supplementation with siderophore voids this resistance. We demonstrated that the absence of mitochondrial siderophore in mice enhances their ability to resist infection.

When we exposed mice deficient for mitochondrial siderophore to systemic infection by E. coli, the animals resisted infection. E. coli bacteria had less iron to access from mitochondrial siderophore-deficient mice.

Do mice normally suppress synthesis of their siderophores when they are infected with bacteria?

Yes, to prevent bacterial acquisition of endogenous siderophores. In addition to the suppression of the endogenous mitochondrial siderophore, mice also secrete lipocalin 24p3, which sequesters bacterial siderophores.

The action of lipocalin significantly reduced the mortality of the mice from the E. coli infection. In fact, some mice were able to recover. The delay of bacterial proliferation provided the immune system time to identify and then neutralize the microbe.

Do you think it will be possible to develop effective therapeutics to combat bacterial infection by blocking bacteria’s access to iron in the body?

Possibly. Mammalian siderophore will be an important target for therapeutics one day because it can be modified to prevent bacteria from acquiring iron while keeping the host’s access to mitochondrial siderophore-bound iron unperturbed.

Any approach that would suppress either mitochondrial siderophore and activate lipocalin-2 would likely slow infection, allowing the host’s immune system to respond.

Would this provide a solution to antibiotic resistant bacteria or would the bacteria be likely to overcome the blocking of access to iron in time?

Perhaps. The siderophore mechanism could be a potential approach to treat some infection that is resistant to antibiotics by using the biology of the bacterium against it.

Such novel approaches would also provide a much-needed alternative to treat those infections that have become antibiotics resistant. However, bacteria continue to evolve and acquire additional mechanisms to circumvent host restriction of iron.

What are your further research plans?

We plan on testing the role of endogenous siderophores in inflammation and viral infections. We are also interested in studying the synergy between siderophore and other molecules that prevent bacterial iron acquisition - for instance, lipocalin 24p3.

Where can readers find more information?

  1. Ganz, T. 2009. Iron in innate immunity: starve the invaders. Curr. Opin. Immunol. 21:63-67.
  2. Cassat, J.E., E.P. Skaar. 2013. Iron in infection and immunity. Cell Host Microbe 13:509-519.
  3. Jones, R., C. Peterson, R. Grady, A. Cerami. 1980. Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth. J. Exp. Med. 151:418-428.

About Dr. Devireddy

Laxminarayana Devireddy, DVM, PhD, is assistant professor of pathology, Case Comprehensive Cancer Center. He earned his DVM from A.P. Agricultural University in Hyderabad, India, and later pursued a master’s degree in virology from the Indian Institute of Science (IISC) in Bangalore.

Devireddy then enrolled in an interdisciplinary graduate program at University of Nebraska Medical Center where he earned a PhD and studied the latency of herpes viruses. His postdoctoral studies were funded by fellowships from Leukemia and Lymphoma Society and Howard Temin Award from the National Cancer Institute.

In the fall of 2006, Devireddy accepted a faculty position in the Department of Pathology/Case Comprehensive Cancer Center at Case Western Reserve University.

At Case he studies regulation of apoptosis by newly discovered lipocalin. He is also interested in analyzing the role of lipocalin in normal physiology and myeloproliferative disease.

April Cashin-Garbutt

Written by

April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.

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Comments

  1. Tom Hennessy Tom Hennessy Canada says:

    One might wonder if the iron levels in the body reflect the ability of the body to resist infection? If one has a 'higher than normal' amount of iron in the body, would the body be hindered in its' ability to amount an effective immune response, sequester iron away from the infection? One might think a simple way of removing iron immediately would be by using phlebotomy, blood donation? This would limit the 'free non liganded iron?

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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