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How Can We Defeat the Growing Threat of Antibiotic Resistance?


Starve them out

Nolan’s chosen strategy uses metals essential to an organism’s survival. “Humans have three to five grams of iron inside our bodies, which is critically important for our health,” she says. “Many kinds of bacteria also need this iron, but it’s hard for them to find it.” During infection, microbes and hosts compete for iron and other metals, and this contest has provided Nolan with ideas for new therapies. In a series of studies, she has investigated the metal-acquisition systems in such pathogenic bacteria as Escherichia coli and Salmonella. Inside the infected host, these bacteria fabricate molecules called siderophores, which are set loose in the environment outside of cells.
“Siderophores scavenge iron from the host, and deliver it to the bacterial cell,” says Nolan. The human immune system fights back through a metal-withholding response, which includes unleashing proteins that can capture certain iron-bearing siderophores. In short, as Nolan puts it, “There’s a total battle for nutrient metals going on. The question is whether the host outcompetes the microbe, or vice versa.” To give an edge to the host, Nolan has been exploring several strategies. One involves tethering antibacterial cargo to siderophores and unleashing them against specific pathogens. Another, in partnership with researchers at the University of California, Irvine, is designed to boost the immune system’s metal-withholding response by generating siderophore-capturing antibodies in the host. In early laboratory tests of this method, Nolan and her partners successfully inhibited the growth of Salmonella. “We are really excited about the possibility of immunizing against bacterial infections,” she says.
Nolan sees great potential in fundamental research aimed at revealing the structural and functional properties of the human immune system’s metal responses. In one recent study, for instance, she discovered that calprotectin, an abundant, metal-sequestering human protein that is present at sites of infection, has uniquely versatile properties that allow it to seize whatever metal an infectious microbe requires for its survival. This is the kind of discovery that might someday generate a new antibiotic therapy. It is another reason why Nolan is confident, she says, that “deciphering the pathways used by organisms and hosts for sequestering nutrient metals will lead to new insights for preventing and treating disease.”

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