New look at how resistant bugs dodge drugs

Yale biologists have opened a new front in the war on antibiotic-resistant bacteria by creating the first high-resolution pictures that show how some resistant bacterial strains, which threaten to undo years of progress against infectious disease, thwart commonly used antibiotics.

The new research, published in the April 22 issue of Cell, provides scientists with a fresh battle plan for creating new antimicrobial drugs.

Many widely used antibiotics work by latching onto and inhibiting ribosomes, the protein factories present in all cells. Using X-ray crystallography, 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, determined the atomic-level structure of five common antibiotics when the drugs were bound to the ribosomes of sensitive or resistant bacteria.

Although the antibiotics used in the study have quite different chemical structures, Steitz and Moore found that they all bind to the same site on the ribosome’s large subunit and that resistance to all of them is generated by the same change in just one of 3,000-plus RNA nucleotides that, along with 21 proteins, make up the enormous structure.

“We found that the resistance results from a mutation in the RNA part of the ribosome that puts an extra bump on its surface that pushes the drug a little further away from its preferred site than it would like to be,” Moore says. This minor change causes antibiotics to lose their grip on the ribosome. The binding of one drug used in the study, azithromycin, was reduced by a factor of 10,000 on ribosomes of resistant bacteria.

Bulges of the kind found by Steitz and Moore are so effective at protecting bacteria that they have developed two ways to add them. Some, such as those examined in the new study, mutate their ribosomal RNA, but more commonly they acquire an enzyme that adds the bump to unmutated RNA.

Understanding the structural basis of resistance suggests how to beat it: chemists can build new antibiotics one atom at a time, tailoring the chemical shape of the drug to accommodate that extra bump. Similar approaches have resulted in new drugs to treat AIDS and cancer.

“Without detailed structure information, you do what medicinal chemists have done for years—you randomly change the antibiotics in a kind of blind way, and keep testing them,” Moore says. “Now, we can make guided changes based on the structure.”

Five years ago Steitz and Moore’s lab beat out the competition in a hotly contested international race to solve the high-resolution structure of the bacterial ribosome’s large subunit. They quickly joined with several Yale colleagues to found Rib-X Pharmaceuticals, and the New Haven-based startup has been pursuing new antibiotic drugs ever since.

According to structural biologist Jamie H.D. Cate of the University of California at Berkeley, the quality of Steitz and Moore’s structures makes them particularly valuable. “Their structures are really gorgeous,” Cates says. “Steitz and Moore see more detail in the ribosome than anyone else can see, and getting those details right is important for drug discovery.”