Using X-ray crystallography, researchers at Yale have "seen" the structural basis for antibiotic resistance to common pathogenic bacteria, facilitating design of a new class of antibiotic drugs, according to an article in Cell.
In recent years, common disease-causing bacteria have increasingly become resistant to antibiotics, such as erythromycin and azithromycin. Although the macrolide antibiotics in this group are structurally different, all work by inhibiting the protein synthesis of bacteria, but not of humans. They bind tightly to an RNA site on the bacterial ribosomes, the cellular machinery that makes protein, but not to the human ribosomes.
Bacteria can become resistant to antibiotics in several different ways. When bacteria mutate to become resistant to one of these antibiotics, they usually are resistant to all antibiotics in the group.
Studies led by Sterling Professors Thomas A. Steitz and Peter B. Moore in the departments of molecular biophysics and biochemistry and chemistry at Yale illuminate one of the ways that bacteria can become resistant to macrolide antibiotics.
"A major health concern of antibiotic resistance is that two million people every year get infections in hospital facilities and 90,000 per year die from them," said Steitz. "Macrolide-resistant Staphylococcus aureus is the most common of these infections."
Some of the clinically important bacteria are resistant because of mutation of a single nucleotide base, from an A to a G, in the site where macrolide antibiotics bind to the ribosome. The Yale group was able to "see" structural alterations when antibiotics were bound to ribosomes with different sensitivity to the drugs because of mutation.
They can now explain why that mutation has the effect that it does. "The mutant G has an amino group that pokes into the center of the macrolide ring, causing it to back off the ribosome by an Angstrom or so," said Steitz.