Antibiotic-resistant ribosomes unmasked

Five years ago, Yale scientists made a splash with the long-sought atomic structure of the large subunit of the ribosome, the protein-synthesizing factory of the cell and a target for many antibiotics (See “Yale Researchers Solve Structure of the Ribosome,” Fall 2000/ Winter 2001). It was the largest asymmetric structure to be solved up to that time, and the work, coming from the laboratories of Thomas A. Steitz, Ph.D., Sterling Professor of Molecular Biophysics and Biochemistry and a Howard Hughes Medical Institute investigator, and Peter B. Moore, Ph.D., Sterling Professor of Chemistry and professor of molecular biophysics and biochemistry, settled many long-standing questions about protein synthesis.

This spring the Yale group offered a new collection of structures that explain how some bacteria escape the killing effects of some antibiotics. With antibiotic resistance threatening to undo years of progress against infectious disease, the work provides a road map to new antimicrobial drugs.

Many commonly used antibiotics bind to the same large pocket in the bacterial ribosome and block its ability to synthesize proteins. In a study published in the April 22 issue of the journal Cell, Steitz and Moore investigated how azithromycin and four other antibiotics bind to the ribosome in drug-resistant and nonresistant bacteria. All are affected by the same crucial change in just one of the 3,000-plus RNA nucleotides that make up the large subunit.

“We found that mutations creating resistance result in the insertion of one extra polar bump into the drug binding site that pushes a bound drug a little further away from its preferred position than it would like to be,” said Moore. “The shape and charge complementarity go from nice to not quite so nice, and you go from sensitive to resistant because the amount of drug it now takes to inhibit these bacteria is more than patients can tolerate.”

Knowing the problem suggests its solution—redesign antibiotics so they can fit around the bump. Now researchers can exploit structure-based drug design, a technique that has yielded successful treatments for aids and cancer. That effort will continue close to home, at Rib-X Pharmaceuticals, the New Haven startup that Steitz, Moore and several Yale colleagues co-founded back in 2001, in the wake of solving their first ribosome structure.