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Feb 25, 2008

Making Resistance Futile

  • The phenomenon of multiple drug-resistance among bacteria is a public health concern and it is spreading rapidly in the biosphere. From Mycobacterium tuberculosis to Staphylococcus aureus, life threatening bugs resistant to the most powerful antibiotics in a physician's arsenal are popping up everywhere. For the first time, researchers are getting a handle on how it is that lowly bacteria outwit the best efforts of scientists. The results are troubling. Writing in EMBO Reports, Frédéric Dardel and colleagues at the University Paris Descartes describe the crystallization analysis of an antibiotic-modifying enzyme known as an acetyltransferase, which renders antibiotics useless by adding an acetyl group to them. Studying both broad and narrow range forms of the enzyme, Dardel discovered the key to the acetyltransferase's ability to operate on multiple chemicals. The answer is the relative plasticity of the active site, a quality that allows a single enzyme to accommodate, and thus act on, multiple antibiotic substrates. The range of compounds that the acetyltransferases could work on raised eyebrows. Their ability to alter single classes of chemically related antibiotics, such as aminoglycosides (for example, streptomycin, kanamycin), was not surprising, but the ease with which they acted on even structurally unrelated fluoroquinolones was. One hopeful aspect of the work was the research team's analysis of the enzyme bound to antibiotics in the act of reacting (transition state), giving clues to the chemical mechanism of catalysis and strategies for designing drugs that will thwart the reactions caused by the enzyme.

    EMBO reports