Antibiotics save lives, but they are not fail-safe. Even when microbes have not acquired genetic mutations that prevent drug use, a hallmark of antibiotic resistance, medications do not always eliminate infections. A new study identifies a surprising reason why: at infection sites, antibiotics change the natural mixture of chemicals made by the body in a way that protects infected bacteria. They also frustrate the ability of the host's immune cells to fight against intruders.
These findings, published Thursday in Cell Host & Microbe could help scientists "build more effective treatments," says James Collins. a biological engineer at the Mbadachusetts Institute of Technology and lead author of the article. Later, it is possible to administer antibiotics along with other substances that mitigate these changes or have the opposite effect, making the drugs more effective, he says.
Collins and his colleagues at the MIT Broad Institute, Harvard University and the University of California, San Diego, infected mice with Escherichia coli bacteria and gave some of them antibiotics. Then, the scientists took tissue samples from the mice and badyzed the levels of certain body chemicals, known as metabolites, that bacteria can use to grow and multiply. At sites of their infections, mice fed antibiotics had higher levels of some metabolites compared to drug-free mice. The levels were also higher than what the scientists detected in healthy mice.
To see if metabolites modified the efficacy of antibiotics, Collins and colleagues added these isolated chemicals to E. coli grown in laboratory dishes. They discovered that they needed to add higher drug concentrations to kill the bacteria when some of the chemicals were present. In other words, chemicals that had accelerated in infected animals treated with antibiotics, ironically, made bacteria less susceptible to drugs.
These chemical changes were not caused by bacterial cells, but by the animals themselves. Cells The researchers discovered it after giving antibiotics to the so-called "germ-free" mice that had no bacteria and experienced the same chemical changes. "It really is amazing," says Eric Brown, the Canada Research Chair in Microbial Chemical Biology at McMaster University in Ontario, who was not involved in the research. "Antibiotics are supposed to be 'magical bullets' aimed at bacteria but not at the person suffering from the infection … Well, this work suggests that more is happening, on the host side, than we could to have thought ".
It is not clear to what extent these changes could reduce the efficacy of antibiotics in infected persons. "We suspect that the strength of this effect will really depend on the type of infection and the types of antibiotics used," says one of the article's co-authors, Jason Yang, a postdoctoral bioengineer at MIT. Some drugs, such as streptomycin, are very sensitive to local chemical changes, he says, so these effects could significantly affect the medication, but more studies are needed.
Collins is also unsure of how chemicals cause these effects. But he notes that some of the compounds slow down aspects of bacterial metabolism, making antibiotics less lethal. Most antibiotics accelerate bacterial metabolism while destabilizing the metabolic process, leading to the accumulation of toxic molecules within the bacteria that help kill them. With this attenuated process, bacteria survive more easily.
Host cells are unlikely to produce these metabolites as part of a targeted reaction, says Yang. "We do not believe that this is a programmed biochemical response, that when a host cell sees an infection and sees an antibiotic, that is what it will produce," he says. Instead, it is likely that "the non-specific side effects of these antibiotics in the presence of insects are causing other physiological changes that we do not know". And these metabolites could be released as a kind of by-products. "
Antibiotics also seem to interfere with the activity of host immune cells against infection When Collins and his team added antibiotics to the immune cells of mice called macrophages , the cells consumed less oxygen, which is necessary for the activity that kills the bacteria.They then exposed the macrophages that had been treated with antibiotics to E. coli .They found that, compared to macrophages that did not they had been treated with antibiotics, those who had been exposed to the drugs swallowed and destroyed fewer bacteria.
Yang emphasizes that these findings do not mean that antibiotics are useless. "Antibiotics work very, very well," he says. For the vast majority of infections, [when] we administer an antibiotic locally, it will clear the infection. "But the findings suggest that infections are complicated environments, and that antibiotics are more influential than bacterial cells, often in unexpected ways. "That's one of the really important concepts that I hope we can convey, it's complicated and the complicated parts do matter," he says.