Research Reveals How Antibiotics Work
The innocent days when antibiotics
worked reliably and scientists could assume they worked directly—like popping a
balloon—are fading. As resistance mounts, understanding how antibiotics really
work could be the key to sustaining their efficacy.
A new study provides direct evidence
that antibiotics sometimes do not kill outright. Rather, they create
conditions for bacterial demise by upsetting their metabolism, leading bacteria
to a state of oxidative stress that ultimately breaks down their DNA and other
key molecules.
The antibiotics tested in the
study—ampicillin, kanamycin, and norfloxacin—did not kill just by attacking
their distinct direct targets. Instead, they killed bacteria like infections
often kill us: by wreaking general havoc that allows organ failure to deliver
the finishing blow. People do not necessarily die from infections; they die
from complications due to those infections. These bacteria did not die from
antibiotics; they died from complications due to antibiotics.
The findings, published in Cell
Reports, have several specific implications for how antibiotics can be used
and improved, said lead author Peter Belenky, assistant professor of molecular
microbiology and immunology.
"One option to overcome the
antibiotic resistance crisis is to design new antibiotics, but that's not
really happening at this point," Belenky said. "But what we can do is
figure out how to use our current arsenal of antibiotics better. Understanding
how antibiotics kill bacteria—the very specific pathways—becomes very important
for figuring out ways we can potentiate antibiotic activity with current
antibiotics."
Stressed to Kill
In recent years as scientists have
proposed more sophisticated hypotheses about what antibiotics do, they have
made observations suggesting that bacterial death stems from major metabolic
disruptions. Belenky's study, as well as a paper he co-authored earlier this
year in the Proceedings of the National Academy of Sciences, were
the first to test these hypotheses by making direct measurements of the
metabolic products of Escherichia coli (E. coli) as
it suffered antibiotic attack. He did much of the work while at Boston
University in the lab of co-corresponding author James Collins, who is now at
MIT, and some of the work at Brown with research assistant Benjamin Korry.
"There were a lot of hypotheses
about what antibiotics could do to bacterial metabolism, but we didn't really
know," Belenky said."So we set out to directly test the metabolic
consequences of antibiotic treatment."
In all, Belenky and his co-authors
tracked levels of nearly 200 metabolites in the cell. What the researchers
noticed right away from their data was that metabolism didn't categorically
decline after the bacteria were exposed to the medicines. Instead, the direct
chemical evidence showed that the bacteria ramped up a key energy generating
process called the TCA cycle.
The TCA cycle in overdrive produces
"oxidative stress" in the form of an increase in by-product chemicals
called "reactive oxygen species." The bacteria, the data showed, try
to protect themselves by producing more of a protective substance called
glutathione, but are eventually overwhelmed.
The team also directly observed the
tell-tale damage that oxidative stress does to proteins, lipids, and the
especially important molecules DNA and RNA. By sending in glowing proteins that
attach to fractured DNA, for example, Belenky and his colleagues could directly
observe fatal double-strand breaks in the DNA of E. coli subjected
to antibiotics. These breaks occurred much less frequently in E. coli left
unhindered by the antibiotics.
News to Use
Belenky said there are four main
implications from the findings.
§
More mutations: The finding that
antibiotics damage DNA suggests that sub-lethal doses may cause genetic
mutations that may promote antibiotic resistance.
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Early detection: To assess whether
antibiotics work against bacteria, scientists usually wait hours to see if they
die. Instead they could tell in minutes by looking for changes in metabolism.
§
A pump to prime: If TCA in overdrive
contributes to bacterial death, maybe finding additional ways to boost that
cycle can make antibiotics more effective.
§
Smarter combinations: Antibiotics are
often given in combination. Ones that tamp down TCA could negate the ones in
this study, undermining treatment. The more doctors know about antibiotic
function, the more effective they can be when combining them.
Belenky said he hopes the findings
can lead to more effective treatments for patients fighting infections.
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