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On a computer screen, Rib-X scientist Brian Wimberly rotates a bacterial ribosome, a tangled, multihued mass. He zooms in, flying through the green and yellow outer shell, deep into the red and purple heart. He points to a hexagon jutting into a vast black hole. The hexagon is a single base of RNA, an adenine labeled A2058. Wimberly clicks his mouse and a blue filament appears next to it, an antibiotic of the macrolide class. This drug binds to A2058 deep inside the ribosome, blocking protein production. No protein means no life for the bacteria.
Human ribosomes, in contrast, display a different base at that location, a guanine. The substitution subtly alters the shape of the protein-making center of the ribosome, rendering our cells impervious to macrolides. In the never-ending evolutionary arms race, though, bacteria exposed to macrolides learn this trick, too. They change adenine to guanine, and bing: antibiotic resistance.
Such miniscule alterations, along with other types of antibiotic resistance, account for some 99,000 deaths in the United States each year. About half of antibiotics work by interfering with bacterial ribosomes, and the scientists at Rib-X exploit the deep structural knowledge Steitz's team provided to invent better ones. The 40-person company has two new antibiotics poised for pivotal phase three studies, with two more ready for human safety tests.
Rib-X CEO Susan Froshauer says there's been but a trickle of new antibiotics from big pharma, hampering efforts to treat, for example, drug-resistant tuberculosis and nasty hospital-borne bacteria like Staphylococcus aureus. “These are serious, serious infections,” says Froshauer.
Steitz didn't tackle the ribosome to make new drugs, but once he did, he understood the opportunity. In eight years, Rib-X scientists have determined the structures of some 400 ribosome-antibiotic complexes. It took the Yale team five tough years to solve just one of them.
Steitz talks about the company as a parent might talk about a child. “I've been so pleased,” he beams. During the Yale press conference announcing his prize, Steitz repeatedly bent questions about himself into praise for Rib-X.
Maybe his Midwestern roots are responsible for that self-effacing manner. In any case, Steitz is right at home in Connecticut now, with a house on the coast, the sailboat he enjoys with Joan and their son Jon, the roses, the 600-bottle wine cellar, the gourmet-chemist meals, a warm coterie of life-long friends and colleagues, a view from the top. Taking a rare moment to survey his career and the ever-expanding knowledge of the ribosome pouring in—his original publication has been cited 1,500 times—Steitz knows his work isn't done, saying, “There's always just one more step.”