Yale Scientists 'See' Basis Of Antibiotic Resistance

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Source: Yale UniversityPrint this pageDate: 2005-05-10

URL: http://www.sciencedaily.com/releases/2005/05/050509174722.htm

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Yale Scientists 'See' Basis Of Antibiotic Resistance

New Haven, Conn. -- 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 A. Steitz and B. 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.

The change of that one base in the ribosomal RNA reduced the ability of the

antibiotic to bind by a factor of 10,000.

Mutation of this type happens naturally, but rarely -- only one in 100,000 to

one in 10,000,000 bacterial mutations will cause this kind of resistance.

However, each bacterium can divide as often as every 20 minutes, allowing

one with a resistant mutation to rapidly cause a dangerous infection.

Steitz and are among the co-founders of Rib-X, a New Haven-based

start-up company that has exclusive license to the high-resolution crystal

structure of the ribosome they revealed. Rib-X is utilizing this information to

create new antibiotics; they project Phase-I trials of their first drug to begin

in

early 2006.

Daqi Tu, a student, and Gregor Blaha, a postdoctoral fellow in molecular

biophysics and biochemistry and associate of the Medical

Institute, are co-authors on the study.

Funding for this research was obtained from the National Institutes of Health

and the Agouron Institute.

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Citation: Cell 121(2): (April 22) 2005.