Antibiotic-resistant forms of Staphylococcus aureus (staph) have made staph the leading cause of infectious heart disease, the No. 1 cause of hospital-acquired infection, the leading cause of pus-forming skin and soft-tissue infections, and one of four leading causes of food-borne illness.
By some estimates the number of deaths caused by the antibiotic-resistant strain MRSA (methicillin-resistant Staphylococcus aureus) exceeds the number of deaths attrib-utable to HIV/AIDS in the United States.
“Staph is arguably the most important bacterial pathogen impacting the public health of Americans,” says Eric Skaar, assistant professor of microbiology and immunology. “And it seems as if complete and total antibiotic resistance of the organism is inevitable at this point.”
That dire outlook has motivated Skaar, postdoctoral fellow Brian Corbin, and a team of researchers in their search for new techniques to use against staph infections. The researchers reasoned that proteins present at the site of a staph infection might be important to the battle between the bug and the immune system.
Even bacteria need to eat. And one of the ways our bodies defend themselves against these foes is to “hide” their food, particularly the metals they need to survive. Vanderbilt researchers discovered that a protein inside certain immune-system cells blocks growth of staph bacteria by sopping up manganese and zinc–supporting the notion that binding metals to starve bacteria is a viable option for fighting localized bacterial infections.
They took advantage of the fact that staph forms abscesses –pimple-like infected areas–in internal organs like the liver. “Because we can tell exactly where the infection is, we can look for proteins that are present only at the site of infection,” Skaar says.
Using technology called imaging mass spectrometry, developed at Vanderbilt by Richard Caprioli, the Stanley Cohen Professor of Biochemistry and director of the Mass Spectrometry Center, investigators identified dozens of proteins specifically expressed in staph abscesses in mice. They focused on one that was particularly abundant–calprotectin, a calcium-binding protein that has been extensively studied by Walter Chazin, Chancellor’s Professor of Biochemistry and Physics and director of Vanderbilt’s Center for Structural Biology. Calprotectin is known to inhibit bacterial and fungal growth in test tubes, but how it kills bugs was unclear.
The team demonstrated in a series of experiments that calprotectin inhibits staph growth by binding–chelating–nutrient metals, specifically manganese and zinc.
“It basically starves the bacteria by stealing its food,” Skaar says.
To confirm calprotectin’s role, investigators infected mice lacking the calprotectin gene and showed that those animals were more susceptible to abscess formation than normal mice.
Then researchers examined levels of metals in staph abscesses in normal and cal-protectin-negative mice. Free manganese and zinc were strikingly absent in the abscesses of normal mice, but present in abscesses missing calprotectin, demonstrating the critical role of calprotectin in binding these two metals.
Calprotectin makes up about half the internal content of neutrophils, the primary immune cells that respond to a staph infection. The researchers propose that calprotectin is a second weapon neutrophils employ as they wage battle in the abscess. First, neutrophils try to gobble up the bacteria. If they fail and die (staph is expert at secreting toxins that kill neutrophils), then they spill their guts, which are filled with metal-binding calprotectin sponges that soak up the metals.
“The neutrophil gets the last laugh,” Skaar says.
These findings suggest that drugs which bind metals, as calprotectin does, would make good antibiotics. “If we can figure out how to make a molecule that transiently binds metals and that can be targeted to abscesses, I think that would be a great drug,” Skaar says.
Findings are detailed in a study published in the Feb. 15 issue of the journal Science, with Corbin as lead author and Skaar as senior author.
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