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.

Brandeis University

Related Bacteria Articles from Brightsurf:

Siblings can also differ from one another in bacteria
A research team from the University of Tübingen and the German Center for Infection Research (DZIF) is investigating how pathogens influence the immune response of their host with genetic variation.

How bacteria fertilize soya
Soya and clover have their very own fertiliser factories in their roots, where bacteria manufacture ammonium, which is crucial for plant growth.

Bacteria might help other bacteria to tolerate antibiotics better
A new paper by the Dynamical Systems Biology lab at UPF shows that the response by bacteria to antibiotics may depend on other species of bacteria they live with, in such a way that some bacteria may make others more tolerant to antibiotics.

Two-faced bacteria
The gut microbiome, which is a collection of numerous beneficial bacteria species, is key to our overall well-being and good health.

Microcensus in bacteria
Bacillus subtilis can determine proportions of different groups within a mixed population.

Right beneath the skin we all have the same bacteria
In the dermis skin layer, the same bacteria are found across age and gender.

Bacteria must be 'stressed out' to divide
Bacterial cell division is controlled by both enzymatic activity and mechanical forces, which work together to control its timing and location, a new study from EPFL finds.

How bees live with bacteria
More than 90 percent of all bee species are not organized in colonies, but fight their way through life alone.

The bacteria building your baby
Australian researchers have laid to rest a longstanding controversy: is the womb sterile?

Hopping bacteria
Scientists have long known that key models of bacterial movement in real-world conditions are flawed.

Read More: Bacteria News and Bacteria Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to