Scientists Locate A Genetic 'On/Off Switch' In Diphtheria; Find May Yield Antibiotics That Won't Boost Bacterial Resistance

November 05, 1998

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 by sequestering iron. The battle then escalates, with the bacteria retaliating by attacking the body's cells in the hope of scavenging some iron.

Scientists say the new findings raise the prospect of a novel class of antibiotics that won't foster bacterial resistance; current-generation treatments can lead to resistance in as little as six months. "Today's antibiotics actually strengthen resistant strains of bacteria," notes Gregory Petsko, Gyula and Katica Tauber Professor of Biochemistry and Molecular Pharmacodynamics and director of the Rosenstiel Center at Brandeis. "When they kill off normal strains while leaving resistant strains unaffected, they're essentially selecting for the resistant strains' survival."

"The potential new class of drugs here would be better because rather than killing the bacteria, they'd simply prevent the bacteria from becoming virulent and killing you," adds Petsko, who was not involved in this work.

Once 95 percent lethal, diphtheria is no longer a major concern in the developed world. But the former Soviet Union has experienced a sharp recurrence of the disease during the 1990s, and public health officials are watching with alarm as the outbreak trudges westward toward Europe.

Ringe was joined in the work by Andre White and Xiaochun Ding at Brandeis and Johanna C. vanderSpek and John R. Murphy at Boston University. The research was sponsored by the National Institute of Allergy and Infectious Diseases and the Lucille P. Markey Charitable Trust.
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Brandeis University

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