One of the ways we defend ourselves against bacterial foes is to “hide” their food, particularly the metals they crave. A multi-disciplinary team led by Vanderbilt University investigators has now discovered that a protein inside certain immune system cells blocks the growth of “staph” bacteria by sopping up manganese and zinc.
The findings, reported Feb. 15 in Science, support the notion that binding metals – to starve bacteria – is a viable therapeutic option for treating localized bacterial infections. New treatment strategies are urgently needed to combat the surging number of infections and deaths caused by antibiotic-resistant forms of Staphylococcus aureus (staph), such as MRSA.
If recent estimates are accurate, the number of deaths caused by MRSA exceeds the number of deaths attributable to HIV/AIDS in the United States.
“Staph is arguably the most important bacterial pathogen impacting the public health of Americans,” said Eric Skaar, Ph.D., assistant professor of Microbiology and Immunology and senior author of the study.
Staph is the leading cause of pus-forming skin and soft tissue infections, the leading cause of infectious heart disease, the number one hospital-acquired infection, and one of four leading causes of food-borne illness.
“And it seems as if complete and total antibiotic resistance of the organism is inevitable at this point,” Skaar said.
The dire outlook motivates Skaar and his colleagues in their search for new antibiotic targets.
Skaar and Brian Corbin, Ph.D., postdoctoral fellow and lead author of the report in Science, reasoned that proteins present at the site of a staph infection might be important to the battle between the bug and the immune system, and might therefore make good targets for therapeutics. 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 said.
Using sophisticated technology called “imaging mass spectrometry,” the investigators identified dozens of proteins specifically expressed in staph abscesses in mice. They decided to focus on one that was particularly abundant.
The protein turned out to be calprotectin, which was discovered as a calcium-binding protein about 20 years ago and 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 in vitro and in vivo experiments that calprotectin inhibits staph growth and that it does this by binding – chelating – nutrient metals, specifically manganese and zinc.
“It basically starves the bacteria by stealing its food,” Skaar said.
Calprotectin makes up about half of the internal content of neutrophils, the primary immune cells that respond to a staph infection. The investigators 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 quipped.
“The work is a phenomenal merger of several cutting edge technologies, which collectively allow an unprecedented view of the host-pathogen interface,” said Paul Dunman, Ph.D., assistant professor of Pathology and Microbiology at the University of Nebraska Medical Center, and a co-author of the Science paper. “This discovery could lead to a new way to treat staph infections.”
The findings suggest that drugs that bind metals – like 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 said.
Walter Chazin, Ph.D., Richard Caprioli, Ph.D., and members of their teams at Vanderbilt were key to the studies, as were collaborators at the University of Aberdeen, Scotland, the University of Nebraska Medical Center, the University of Muenster, Germany, and Applied Speciation and Consulting in Washington. The research was supported by the Searle Scholars Program, the Burroughs Wellcome Fund, the National Institutes of Health, and the Department of Defense.
Journal
Science