Volume 85 Issue 37 | p. 8 | News of The Week
Issue Date: September 10, 2007

All Roads Lead To Hydroxyl Radicals

Compounds with different targets trigger common killing mechanism
Department: Education | Collection: Green Chemistry
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Credit: Adapted from Cell
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Credit: Adapted from Cell
Collins (standing left), grad students Michael Kohanski (seated left) and Carolyn Lawrence, and postdoc Daniel Dwyer figured out that bactericidal antibiotics have a common death mechanism.
Credit: Kathleen Fink/Boston University
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Collins (standing left), grad students Michael Kohanski (seated left) and Carolyn Lawrence, and postdoc Daniel Dwyer figured out that bactericidal antibiotics have a common death mechanism.
Credit: Kathleen Fink/Boston University

THE MAJOR CLASSES of bacteria-killing antibiotics may not be as different as previously thought. Antibiotics are usually classified by their primary target, DNA replication, protein synthesis, or cell-wall synthesis. James J. Collins, professor of biomedical engineering at Boston University, and coworkers now report that these seemingly different antibiotics trigger a common cell death mechanism downstream of their initial targets, generating hydroxyl radicals that damage DNA, proteins, and lipids (Cell 2007, 130, 797). The findings point the way to improving existing antibiotics.

Scott F. Singleton, an associate professor of medicinal chemistry and natural products at the University of North Carolina School of Pharmacy, calls the results "wonderfully unexpected, but in a way that makes one say, 'Of course, why didn't we see that before?' "

The hydroxyl radicals are the product of an oxidative damage pathway, the authors find. The interaction between each of the antibiotics and its target triggers the tricarboxylic acid (TCA) cycle in as-yet-unknown ways. The TCA cycle produces the reduced form of the cofactor nicotinamide adenine dinucleotide (NADH), which shuttles electrons down the electron transport chain of the respiratory pathway. Increased electron transport activity stimulates the production of superoxide, which in turn attacks iron-sulfur clusters in proteins. The Fe2+ that is liberated from these proteins fuels the Fenton reaction, in which Fe2+ reacts with hydrogen peroxide to form hydroxyl radicals. These hydroxyl radicals wreak havoc on bacterial DNA, proteins, and lipids, ultimately killing the cell.

Some antibiotics inhibit cell growth rather than killing the bacteria outright. These so-called bacteriostatic antibiotics don't stimulate the hydroxyl radicals, Collins says, nor do sublethal concentrations of bactericidal antibiotics.

This work "foreshadows the development of adjuvants for antibiotic chemotherapy," Singleton says, referring to small molecules that could enhance the performance of existing antibiotics. Such a prospect has not been lost on Collins. For example, the protein RecA serves as a gatekeeper to the so-called SOS damage response that bacteria muster to repair their DNA. A small-molecule RecA inhibitor used in combination with existing antibiotics could make for "super" antibiotic duos, Collins says.

Collins doesn't think that this hydroxyl radical pathway will help against already-resistant bugs because most resistance mechanisms target the interaction between the drug and its primary target. "We think that this pathway is actually a downstream consequence of the interactions of these antibiotics with their respective targets," he says. "If resistance has already emerged, it's likely that this pathway is not being triggered." Exploiting this pathway, however, might stave off the development of resistance in the first place, Collins notes.

Many scientists have been puzzled that "nature has devised antibiotics that interfere with only a handful of cellular targets in the bacteria," says Shahriar Mobashery, a chemist who studies antibiotics and antibiotic resistance at the University of Notre Dame. The paucity of targets has been hailed as a reason we might run out of clinical options for treating bacterial infections. "Perhaps the triggering of this oxidative damage is at play," Mobashery says. "Perhaps that triggering event is seen only with inhibition of a handful of cellular targets."

 
Chemical & Engineering News
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