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Radicals unite antibiotics

September 6, 2007 By Mary Muers This article courtesy of Nature News.

Drugs that target different pathways share a way to kill bacteria.

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The discovery of a common mode of killing shared by different types of antibiotic could lead to the creation of superdrugs, researchers suggest.

Antibiotics are known to attack different vital processes in bacteria. But a study published in Cell1 today has revealed that three major classes of unrelated drugs use the same ultimate weapon to finish off the infectious critters. All of them force bacteria to create killer bursts of oxygen-containing molecules called hydroxyl free radicals.

Highly reactive free radicals, which have been linked to cancer and ageing in the past, can cause lethal damage to DNA, proteins and fats.

Every antibiotic used in the clinic has a limited shelf-life — it is only a matter of time before some bacteria become resistant. So chemists are engaged in an ongoing battle to create new types of drug.

The finding could offer a completely new method to go about designing antibiotics, and a way to boost the potency of current drugs. Combining a dose of traditional antibiotic with a drug that blocks bacterial defences against free radicals could increase the killing power of treatments.

From start to finish

In their quest for novel antibiotics, James Collins and his team at the Boston University, Massachusetts, decided to pick apart the sequence of events leading from drug treatment to cell death.

They had previously spotted that one type of antibiotic, which interferes with DNA production in bacteria, causes release of radicals. When they used a fluorescent dye that lights up in the presence of hydroxyl molecules, the researchers were surprised to discover that the same free radicals appeared if bacteria were treated with antibiotics that instead attack the cell wall or the protein-making machinery.

These three classes of antibiotics had generally been thought of as very different from each other, and this study is the first indication that they share a modus operandi.

Only bactericidal antibiotics — a group that kills off bacteria and includes penicillin — use this strategy, the team found. Bacteriostatics, drugs that simply halt bacterial growth, didn't trigger radical release.

Superdrug

Collins suggests that chemists could turn a classical antibiotic such as ciprofloxacin into 'super-cipro' by adding chemicals to stop the DNA-repair pathway that bacteria usually use to fight free-radical damage.

Scott Singleton, a researcher at the University of North Carolina in Chapel Hill who is looking into ways to block DNA repair in bacteria, says the exciting discovery could also allow researchers to look again at old drugs that had been shelved due to their toxic effects at high doses. Making such drugs more potent against bacteria could allow lower doses to be used in people, he explains. "It's relatively easy to discover something that kills bacteria, but much harder to do so safely inside the human body," he notes.

Gerry Wright, who works on antibiotic biochemistry at McMaster University in Hamilton, Ontario, says "this is exactly what the field of antibiotic research needs at this time — a fresh look at things we thought we really 'knew'." He adds, "even after more than 60 years of work on antibiotics, there is still so much we don't understand, and this new knowledge can help move the field in an unexpected direction".

References

  1. Kohanski, M. A. et al. Cell 130, 797-810 (2007).

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