Discovery of iron-acquisition pathway suggests new treatments for drug-resistant Staph. infections

February 6, 2003

Researchers at the University of Chicago have discovered how Staphylococcus aureus, a common cause of life-threatening infections, manages to acquire iron from its host's red blood cells, a critical step in causing disease. The discovery, published in the 7 February 2003 issue of the journal Science, suggests new ways to combat this common pathogen, which has grown ominously resistant to antibiotics.

The researchers describe the entire pathway that Staph. aureus uses to burst open red blood cells, capture their hemoglobin, remove the iron-containing heme groups, transport them across the bacterial membrane and extract the iron. They also found that the human pathogens Anthrax and Listeria use the same method.

"It's a beautiful system, a complete and very elegant pathway," said Olaf Schneewind, MD, PhD professor of molecular genetics and cell biology, chairman of the committee on microbiology at the University of Chicago and director of the study. "It involves six different proteins, each with a specific function."

"Our findings could be used to develop drugs that would disrupt the Staphylococcal iron uptake systems," said co-author Eric Skaar, PhD, research associate in molecular genetics and cell biology at the University, "which could, in turn, prevent infection. Having the entire pathway provides us with multiple new drug targets."

With one known exception (Borrelia burgdorferi, the cause of Lyme disease), every pathogen must scavenge iron from its host in order to survive, grow and cause disease. Body fluids from humans and other mammals contain very little free iron, one of the most important defenses against infections. So bacteria have evolved specialized mechanisms to obtain iron from a host's body. Hemoglobin is the most abundent source of iron in the human.

Schneewind and colleagues found that the Staph. aureus genome contains a family of iron-regulated surface determinant (isd) genes that encode factors responsible for binding hemoglobin and bringing the iron it contains across the cell wall and into the cell's interior.

These genes are activated when the bacteria arrive in an iron-poor environment, such as when they infect a surgical wound, the gastrointestinal tract, or virtually any other site in the human body.

The bacteria first secrete hemolysin, a toxin that punches a hole in the outer membrane of red blood cells. Then the protein IsdB binds with the released hemoglobin. IsdA and IsdB remove the four iron-containing heme groups from the hemoglobin and transfer them to IsdC, located within the bacterial cell wall. The proteins IsdD, IsdE and IsdF transport the heme groups through the rigid cell wall and into the cytoplasm, where IsdG binds it. IsdG appears to be involved in removing the iron from heme.

In environments where heme was the sole iron source, bacteria that lacked certain isd genes, or the genes for two enzymes, Sortase A and B, that help anchor the iron-scavenging proteins to unique positions within the cell wall, were unable to grow.

The next step, the researchers said, is to find ways to inhibit this iron-gathering process. Since there is no comparable pathway in humans, drugs that could disrupt the process might provide a safe and effective therapy.

New drugs to fight Staph. aureus are desperately needed. Each year, according to the National Institutes of Health, some 500,000 patients in American hospitals contract a Staph. infection. The bacterium causes illnesses that range from minor skin infections to life-threatening diseases such as pneumonia, meningitis, septicemia, and bone and surgical-wound infections.

Fifty years ago, penicillin could quickly eradicate Staph. infections, but the bacteria quickly developed resistance and by the 1980s penicillin was effective in fewer than 10 percent of cases. So doctors turned to methicillin and other newer antibiotics. In the 1970s, these replacement drugs killed 98 percent of Staph. germs. By the mid-1990s, they were effective against about one-third of infections.

Now, more than 50 percent of all hospital-acquired, and many community-acquired, Staph. aureus infections are resistant to every antibiotic but vancomycin, one of the most expensive antibiotics available. In 2002, the Centers for Disease Control reported the first two documented cases of vancomycin-resistant Staph. aureus.

Additional authors of the study were Sarkis Mazmanian, Andrew Gaspar, Munir Humayun, Piotr Gornicki, Joanna Jelenska and Dominique Missiakas of the University of Chicago and Andrzej Joachmiak of Argonne National Laboratory. The National Institutes of Health funded the research.

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