How to thwart an iron thief

In search of a new class of antibiotics, a Cal Lutheran team takes advantage of its digs in Swenson Science Center.

Eliana Goncuian loads a sample int an ITC instrument during the summer of 2019. ITC is one of two principal techniques utilized by the Hoffmann Lab.

Photo: Courtesy of Kate Hoffmann

Prior to the Swenson Science Center’s opening in August, associate professor Kate Hoffmann ran her research on 1 1/2 lab benches in the 30-year-old Ahmanson building, and her colleague Jason Kingsbury worked out of a converted closet there.

The collaborative labs in Swenson, designed with extensive faculty input, feature a walk-in freezer and room to grow.

One Cal Lutheran student-faculty team is using the elbow room to pursue a novel approach to treating infections from bacteria that have built up resistance to antibiotics.

Supported by a three-year, $195,000 National Science Foundation grant, they are working toward the creation of a new class of antibiotics that renders pathogens harmless by starving them of iron, which is essential to their functioning. In our human bodies, bad actors such as antibiotic-resistant superbugs MRSA and anthrax raid the bloodstream and bones to steal the same iron we need. They carry an enzyme that manufactures a tiny iron thief for the job. Cal Lutheran is taking a hard look at that enzyme.

“Nobody else has done much research on DesD,” said senior Eliana Goncuian, who spent summers creating experimental conditions for it to operate.

DesD serves the researchers as a model for a family of proteins that increasingly is associated with virulent disease. In one part of a paper accepted by the leading journal Biochemistry, she reports on how quickly and how tightly it binds to a substrate to make the iron-pocketing agent.

“We think that the easiest way to inhibit it is through the binding, not necessarily the time,” Goncuian said.

Other members of the Cal Lutheran team are working to confirm which amino acid in DesD’s chain is most important for binding, and eventually to tailor an inhibitor to block it. They’ll draw on Hoffmann’s expertise in characterizing proteins and on Kingsbury’s in synthesizing compounds. A generous donation during the Science Initiative enabled Cal Lutheran to acquire its own isothermal titration calorimetry (ITC) instrument to be housed in the Chemistry Instrumentation Lab after the COVID-19 shutdown restricted access to the one at USC they had been using.

A good inhibitor has to out-compete the bacterial protein. It also must hit a target that is not found all over the body, or it could shut down normal functions and cause side effects. “So you’ve never heard of DesD, and that’s good. Because it’s so unique,” said Hoffmann, the John Stauffer Professor of Analytical Chemistry and principal investigator on the NSF grant. She hopes to map the binding site — a critical step — within five years.

Kevin Matthews is a former editor of CLU Magazine.

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