Study Shows Antibiotics are Unique Assassins

In recent work, biology professor Kim Lewis and senior scientist Iris Keren demonstrate that all antibiotics are not created equal. Photo by Mary Knox Merrill.

In recent years, a body of pub­li­ca­tions in the micro­bi­ology field has chal­lenged all pre­vious knowl­edge of how antibi­otics kill bac­teria. A slew of papers came out studying this phe­nom­enon, sug­gesting that there is a gen­eral mech­a­nism of killing by antibi­otics, says Kim Lewis, Uni­ver­sity Dis­tin­guished Pro­fessor in the Depart­ment of Biology and director of Northeasterns Antimi­cro­bial Dis­covery Center.

The stan­dard thinking at the time was that the three main classes of bac­te­ri­cidal antibi­otics each had a unique way of killing bac­te­rial cellslike spe­cial­ized assas­sins each trained in a single type of weaponry. But this new research sug­gested that all antibi­otics work the same way, by urging bac­te­rial cells to make com­pounds called reac­tive oxygen species, or ROS, which bac­teria are nat­u­rally sus­cep­tible to.

If they were right it would have been an impor­tant finding that could have changed the way we treat patients, says Iris Keren, a senior sci­en­tist in Lewis lab.

And thats exactly how sci­ence usu­ally works, says Lewisthrough chal­lenges to main­stream thinking. But recent results reported by Lewis, Keren, and their research  part­ners in an article pub­lished Friday in the journal Sci­ence sug­gest that this alter­na­tive hypoth­esis doesnt hold up. For example, even bac­teria that are inca­pable of making ROS are still vul­ner­able to antibi­otics. Fur­ther, some antibi­otics can work their fatal magic in both aer­obic and anaer­obic conditionsbut reac­tive oxygen species can only form when theres oxygen to fuel them.

We chose to do the sim­plest and most crit­ical exper­i­ment aimed at fal­si­fying this hypoth­esis, adds Lewis. Killing by antibi­otics is unre­lated to ROS pro­duc­tion, the authors wrote. The find­ings were cor­rob­o­rated by Uni­ver­sity of Illi­nois researchers in another study released on Friday .

The team treated bac­te­rial cul­tures with antibi­otics in both the pres­ence and absence of oxygen. Other than the gaseous envi­ron­ment, the two treat­ments were iden­tical. There was no dif­fer­ence in cell death between the two populations.

Before per­forming these exper­i­ments, Lewis team first looked at sig­nals of a flu­o­res­cent dye, which pre­vious researchers had used as an indi­cator for ROS levels. The team treated bac­te­rial cells with a variety of antibi­otics and mea­sured the strength of this signal. Since antibi­otics were pre­sumed to increase ROS levels, one would have expected increased con­cen­tra­tions of antibi­otics to cor­re­late with stronger sig­nals. How­ever, Lewis group saw no such correlation.

But theres a dif­fer­ence between cor­re­la­tion and direct obser­va­tion, Keren says. In order to sup­port their obser­va­tions with unequiv­ocal data, the team mem­bers phys­i­cally sep­a­rated the cells that had stronger flu­o­res­cent sig­nals from those with weak sig­nals and treated them both with the same antibi­otics. Both pop­u­la­tions suf­fered equiv­a­lent cell death.

The research from Lewis group demon­strates that, con­trary to cur­rent dogma, antibi­otics appar­ently do not kill bac­teria through induc­tion of reac­tive oxygen species, says Steven Projan, vice pres­i­dent for research and devel­op­ment at iMed and head of infec­tious dis­eases and vac­cines at Med­Im­mune, both sub­sidiaries of AstraZeneca. The results shown are rather clear but still leave us with the mys­tery as to how antibac­te­rial drugs help infected people clear bac­te­rial infections. At this point, we should prob­ably dis­pense with the one size fits all approach to bac­te­rial killing by antibi­otics, said Projan, who was not involved in the research.

With these results, Lewis and Keren hope the field will be able to focus its efforts on under­standing the true mech­a­nisms of how antibi­otics wipe out bac­teria in order to effec­tively address chronic bac­te­rial infec­tions, one of the most pressing issues facing public health today.