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New insight into how antibiotics kill might make them deadlier

Cell Press

Scientists have what could be some very bad news for disease-causing bacteria. All three major classes of antibiotics that kill infectious bacteria do so in part by ramping up the production of harmful free radicals, researchers report in the September 7, 2007, issue of Cell, a publication of Cell Press. Because those different types of antibiotics each initially hit different targets, it had been believed they worked by independent means.

The findings could point the way to new classes of antibiotics and to a common method by which existing antibiotics could be made to stamp out bacteria even better, according to the Boston University researchers. Such advances are particularly critical at a time when, according to the Centers for Disease Control and Prevention, nearly all significant bacterial infections in the world are becoming resistant to the most commonly prescribed antibiotic treatments.

"Hydroxyl radicals damage DNA, which turns on the S.O.S. repair response," said James Collins. "Therefore, our findings suggest that if you could shut off the bacteria's repair response, you might make all bactericidal antibiotics more effective and effective at lower doses. You could in essence create a super-Cipro, super-mycins, and so on."

Current antimicrobial therapies fall into two general categories: (1) bactericidal drugs, which kill bacteria with almost complete efficiency, and (2) bacteriostatic drugs, which inhibit their growth, allowing the immune system to clear the infection, Collins's group explained. The targets of bactericidal antibiotics are well studied and predominantly fall into three classes: (1) those that hit DNA, (2) those that hit proteins, and (3) those that hit the bacterial cell wall. In contrast, most bacteriostatic drugs work by blocking the function of ribosomes, which are the sites of protein synthesis. While antibiotics' ability to kill bacteria had been attributed solely to those class-specific drug-target interactions, "our understanding of many of the bacterial responses that occur as a consequence of the primary drug-target interaction remains incomplete," the researchers said.

Collins and his colleagues recently uncovered some evidence that at least some antibiotics might have some other deadly tricks. They showed that one type of antibiotics, including quinolones, which block DNA's replication and transcription into messenger RNA, also causes a breakdown that leads to the production of free radicals. Moreover, they found that those highly reactive chemicals help finish the bacteria off.

In the new study, the researchers wanted to know whether other antibiotics also drive the toxic brew. Indeed, they show, drugs that kill bacteria all do cause a rise in free radicals, and all in the same manner. This is not so for drugs that only stunt bacteria's growth, they report.

"The ever-increasing prevalence of antibiotic-resistant strains has made it critical that we develop novel, more effective means of killing bacteria," the researchers concluded. "Our results indicate that targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response... is a viable means of potentiating all three major classes of bactericidal drugs. Moreover, pathway analyses and systems biology approaches may uncover druggable targets for stimulating hydroxyl radical formation, which could result in new classes of bactericidal antibiotics."

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The researchers include Michael A. Kohanski of Boston University and Boston University School of Medicine in Boston and Daniel J. Dwyer, Boris Hayete, Carolyn A. Lawrence, and James J. Collins of Boston University in Boston.

This work was supported by the National Science Foundation FIBR and Department of Energy GTL programs and NSF award EMSW21-RTG to J.J.C.

Kohanski et al.: "A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics." Publishing in Cell 130, 797-810, September 7, 2007. DOI 10.1016/j.cell.2007.06.049 http://www.cell.com

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