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See Inside Scientific American Volume 309, Issue 2

Antibiotics Are More Mysterious Than They Appear

Scientists still don't know exactly how antibiotics work



Thomas Fuchs

Microbes are tricky critters. Scientists long thought that antibiotics killed bacteria in diverse and specific ways—some prevented bacterial DNA from replicating; others impaired bacterial protein synthesis. Not so, said James Collins, a biomedical engineer at Boston University. In 2007 he published findings that these targeted mechanisms were not the cause of bacterial death after all. His team's study suggested that antibiotics kill by a common mechanism: they boost bacterial levels of molecules known as reactive oxygen species, which fatally corrode the organisms' DNA.

Now Collins's theory is under siege. In March, two independent teams, publishing in Science, showed that antibiotics kill bacteria under oxygen-deprived conditions, which, if Collins is correct, would be impossible: the production of reactive oxygen species depends on oxygen. The two groups also found that bacteria genetically engineered to lack intrinsic antioxidants—substances that protect against reactive oxygen species—are no more sensitive to antibiotics than normal bacteria.

What could explain these discrepancies? A May commentary in Nature Biotechnology posits that because the teams each used different flasks and protocols, batches of bacteria may have been exposed to different oxygen levels, potentially invalidating their findings. Other studies suggest a molecular marker the Collins group used to flag reactive oxygen species is flawed because it also lights up in the presence of other harmless molecules. Colin Manoil, a genome scientist at the University of Washington, worries that the Collins group may simply have misinterpreted its results. “There is a cause-and-effect problem,” Manoil says—even if reactive oxygen species are produced in dying bacteria, they may be the result of impending death, not a cause of it.

The debate is a reminder that even microbes can be unpredictably complex. “Sometimes we fall back on experimental approaches that are not as specific as we would like them to be,” says James Imlay, a University of Illinois at Urbana-Champaign microbiologist and co-author of one of the Science papers. “We're still groping at the edge of the darkness sometimes.”

This article was originally published with the title "A Microbial Mystery."

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