How zinc starves lethal bacteria to stop infection

Contact: Dr Christopher McDevitt christopher.mcdevitt@adelaide.edu.au 61-449-823-946 University of Adelaide

Australian researchers have found that zinc can ‘starve’ one of the world’s most deadly bacteria by preventing its uptake of an essential metal.

The finding, by infectious disease researchers at the University of Adelaide and The University of Queensland, opens the way for further work to design antibacterial agents in the fight against Streptococcus pneumoniae.

Streptococcus pneumoniae is responsible for more than one million deaths a year, killing children, the elderly and other vulnerable people by causing pneumonia, meningitis, and other serious infectious diseases.

Published today in the journal Nature Chemical Biology, the researchers describe how zinc “jams shut” a protein transporter in the bacteria so that it cannot take up manganese, an essential metal that Streptococcus pneumoniae needs to be able to invade and cause disease in humans.

“It’s long been known that zinc plays an important role in the body’s ability to protect against bacterial infection, but this is the first time anyone has been able to show how zinc actually blocks an essential pathway causing the bacteria to starve,” says project leader Dr Christopher McDevitt, Research Fellow in the University of Adelaide’s Research Centre for Infectious Diseases.

“This work spans fields from chemistry and biochemistry to microbiology and immunology to see, at an atomic level of detail, how this transport protein is responsible for keeping the bacteria alive by scavenging one essential metal (manganese), but at the same time also makes the bacteria vulnerable to being killed by another metal (zinc),” says Professor Bostjan Kobe, Professor of Structural Biology at The University of Queensland.

The study reveals that the bacterial transporter (PsaBCA) uses a ‘spring-hammer’ mechanism to bind the metals. The difference in size between the two metals, manganese and zinc, causes the transporter to bind them in different ways. The smaller size of zinc means that when it binds to the transporter, the mechanism closes too tightly around the zinc, causing an essential spring in the protein to unwind too far, jamming it shut and blocking the transporter from being able to take up manganese.

“Without manganese, these bacteria can easily be cleared by the immune system,” says Dr McDevitt. “For the first time, we understand how these types of transporters function. With this new information we can start to design the next generation of antibacterial agents to target and block these essential transporters.”

###

The research has been funded by the Australian Research Council and the National Health and Medical Research Council.

Media Contact:

Dr Christopher McDevitt Research Fellow Research Centre for Infectious Diseases School of Molecular and Biomedical Science The University of Adelaide Mobile: +61 449 823 946 christopher.mcdevitt@adelaide.edu.au

Professor Bostjan Kobe Professor of Structural Biology Australian Infectious Diseases Research Centre School of Chemistry & Molecular Biosciences The University of Queensland Phone : +61 7 3365 2132 b.kobe@uq.edu.au

Robyn Mills Media Officer The University of Adelaide Phone: +61 8 8313 6341 Mobile: +61 410 689 084 robyn.mills@

Green tea chemical combined with another may hold promise for treatment of brain disorders: EGCG, can prevent and destroy a variety of protein structures known as amyloids

2009 study posted for filing

Contact: patti Jacobs pjacobs12@comcast.net 617-864-2712 Boston Biomedical Research Institute

Watertown, MA—Scientists at Boston Biomedical Research Institute (BBRI) and the University of Pennsylvania have found that combining two chemicals, one of which is the green tea component EGCG, can prevent and destroy a variety of protein structures known as amyloids. Amyloids are the primary culprits in fatal brain disorders such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. Their study, published in the current issue of Nature Chemical Biology (December 2009), may ultimately contribute to future therapies for these diseases.

“These findings are significant because it is the first time a combination of specific chemicals has successfully destroyed diverse forms of amyloids at the same time,” says Dr. Martin Duennwald of BBRI, who co-led the study with Dr. James Shorter of University of Pennsylvania School of Medicine.

For decades a major goal of neurological research has been finding a way to prevent the formation of and to break up and destroy amyloid plaques in the brains and nervous systems of people with Alzheimer’s and other degenerative diseases before they wreak havoc.

Amyloid plaques are tightly packed sheets of proteins that infiltrate the brain. These plaques, which are stable and seemingly impenetrable, fill nerve cells or wrap around brain tissues and eventually (as in the case of Alzheimer’s) suffocate vital neurons or brain cells, causing loss of memory, language, motor function and eventually premature death.

To date, researchers have had no success in destroying plaques in the human brain and only minimal success in the laboratory. One reason for these difficulties in finding compounds that can dissolve amyloids is their immense stability and their complex composition.

Yet, Duennwald experienced success in previous studies when he exposed amyloids in living yeast cells to EGCG. Furthermore, he and his collaborators also found before that DAPH-12, too, inhibits amyloid production in yeast.

In their new study, the team decided to look in more detail at the impact of these two chemicals on the production of different amyloids produced by the yeast amyloid protein known as PSI+. They chose this yeast amyloid protein because it has been studied extensively in the past, and because it produces varieties of amyloid structures that are prototypes of those found in the damaged human brain. Thus, PSI+ amyloids are excellent experimental paradigms to study basic properties of all amyloid proteins.

The team’s first step was to expose two different amyloid structures produced by yeast (e.g., a weak version and a strong version) to EGCG. They found that the EGCG effectively dissolved the amyloids in the weaker version. To their surprise, they found that the stronger amyloids were not dissolved and that some transformed to even stronger versions after exposure to EGCG.

The team then exposed the yeast amyloid structures to a combination of the EGCG and the DAPH-12 and found that all of the amyloid structures broke apart and dissolved.

The next steps for the research team will be to explore the mechanism and potency of such a combinatorial therapy for the treatment of diverse neurodegenerative diseases.

“Our findings are certainly preliminary and we need further work to fully comprehend the effects of EGCG in combination with other chemicals on amyloids. Yet, we see our study as a very exciting initial step towards combinatorial therapies for the treatment of amyloid-based diseases,” says Duennwald.

###

Authors of the study include: Martin L Duennwald and Chan Chung from Boston Biomedical Research Institute and Nicholas P Lopreiato, Elizabeth A Sweeny, M Noelle Knight, James Shorter, Huan Wang, and Blake E Roberts from the Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine.

The Boston Biomedical Research Institute is a not-for-profit institution dedicated to the understanding, treatment, and prevention of specific human diseases such as muscular dystrophy, cancer, cardiovascular disease, and Alzheimer’s. For more information, visit us on the web at www.bbri.org.