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Researchers make gains in understanding antibiotic resistance

Howard Hughes Medical Institute researchers chiseling away at the problem of antibiotic resistance now have a detailed explanation of how the drugs' main cellular target in bacteria evolves to become resistant to some of these medications. The findings are already leading to new experimental antibiotics that are being engineered to circumvent resistance, which is a major worldwide health problem.

Led by Thomas A. Steitz, a Howard Hughes Medical Institute investigator at Yale University, and Peter B. Moore, a professor of chemistry at Yale, the research team published its findings in the April 22, 2005, issue of the journal Cell.

Steitz and his colleagues studied the structural basis of bacterial resistance to a group of antibiotics that, while chemically quite different, all jam the activity of the protein-making factory in bacteria in much the same way. They studied the MLSBK antibiotics, an acronym for a group of antibiotics which include macrolides, lincosamides, streptogramin B and ketolides. MLSBK antibiotics work by binding to the RNA, near the peptidyltransferase center, of the large subunit of the ribosome. The ribosome is the molecular machine responsible for translating the genetic information on messenger RNA into the long strings of amino acids called polypeptides that are used to build the cell's enzymatic machinery.

"These antibiotics are clinically very important, and resistance to such antibiotics is a major health problem," said Steitz. "It is becoming critical to understand the precise structural basis of resistance and even more important to do something about it." Steitz cited, for example, recent statistics published in the journal Nature, stating that hospitals in the United States see some two million cases of antibiotic-resistant infections each year; 90,000 patients die annually from such infections.

In their experiments, Steitz and his colleagues used x-ray crystallography to do high-resolution structural anal
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Source:Howard Hughes Medical Institute


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