Antibiotic
resistance is a major and growing problem worldwide. According to the World
Health Organization, antibiotic resistance is rising to dangerously high levels
in all parts of the world, and new resistance mechanisms are emerging and
spreading globally, threatening our ability to treat common infectious
diseases. But how these bacterial resistance mechanisms occur, and whether we
can predict their evolution, is far from understood.
Researchers
have previously shown that one way bacteria can survive antibiotics is to
evolve a "timer" that keeps them dormant for the duration of
antibiotic treatment. But the antibiotic kills them when they wake up, so the
easy solution is to continue the antibiotic treatment for a longer duration.
Now,
in new research
published in the journal Science,
researchers at the Hebrew University of Jerusalem report a startling
alternative path to the evolution of resistance in bacteria. After evolving a
dormancy mechanism, the bacterial population can then evolve resistance 20
times faster than normal. At this point, continuing to administer antibiotics
won't kill the bacteria.
To
investigate this evolutionary process, a group of biophysicists, led by
Professor Nathalie Balaban and PhD student Irit Levin-Reisman at the Hebrew
University's Racah Institute of Physics, exposed bacterial populations to a
daily dose of antibiotics in controlled laboratory conditions, until resistance
was established. By tracking the bacteria along the evolutionary process, they
found that the lethal antibiotic dosage gave rise to bacteria that were
transiently dormant, and were therefore protected from several types of
antibiotics that target actively growing bacteria. Once bacteria acquired the
ability to go dormant, which is termed "tolerance," they rapidly
acquired mutations to resistance and were able to overcome the antibiotic
treatment.
Thus,
first the bacteria evolved to "sleep" for most of the antibiotic
treatment, and then this "sleeping mode" not only transiently
protected them from the lethal action of the drug, but also actually worked as
a stepping stone for the later acquisition of resistance factors.
The
results indicate that tolerance may play a crucial role in the evolution of
resistance in bacterial populations under cyclic exposures to high antibiotic
concentrations. The key factors are that tolerance arises rapidly, as a result
of the large number of possible mutations that lead to it, and that the
combined effect of resistance and tolerance promotes the establishment of a
partial resistance mutation on a tolerant background.
These
findings may have important implications for the development of new
antibiotics, as they suggest that the way to delay the evolution of resistance
is by using drugs that can also target the tolerant bacteria.
Posted by Dr. Tim Sandle