WALTHAM, Mass. -- Researchers at Brandeis University and the Boston University School of Medicine have pinpointed a genetic repressor that can single-handedly morph diphtheria from a mild-mannered bacterium into a lethal parasite. This tiny complex could prove to be the Achilles' tendon of resistant strains of killers such as diphtheria, staph, and flesh-eating bacteria, opening them up to a new class of drugs that won't induce resistance.
The work of the team led by Dagmar Ringe, professor of biochemistry at Brandeis' Rosenstiel Basic Medical Sciences Research Center, appeared in a recent issue of Nature.
Ringe's mapping of the structure of the powerful yet minuscule DtxR repressor -- a billion billion of which could fit on the head of a pin -- doesn't offer insights solely into diphtheria, where DtxR functions. "DtxR is a prototype for the activity of many other virulent bacteria," she says. "Most pathogenic bacteria, including those responsible for tetanus, syphilis, tuberculosis, and botulism, have their own versions of this repressor."
Scientists have known for some time that these bacteria somehow rely on metal ions to become virulent, but the exact mechanism has remained elusive. Ringe and her colleagues used X-ray crystallography to unmask, atom by atom, the exact structure of DtxR, which holds the key to diphtheria's Jekyll-and-Hyde behavior. They found that this repressor, normally tightly latched to the bacterial DNA, has two binding sites for iron ions; when iron grows scarce, the repressor falls off the DNA strand, allowing expression of a gene that goads the bacterium into attacking its host's cells.
"Until now, nobody knew just how bacteria translated a shortage of iron into a headlong assault on the body's tissues," Ringe says.
This chain of events is part of the battle our immune system regularly fights
with a variety of pernicious bacteria. Upon recognizing that iron-craving
bacteria are infiltrating the body, the liver responds
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Contact: Steve Bradt
bradt@brandeis.edu
781-736-4203
Brandeis University
5-Nov-1998