Have you ever had a nasty infection that just won’t seem to go away? Or a runny nose that keeps coming back? You may have been dealing with a bacterium that is tolerant of, though not yet resistant to, antibiotics.
Antibiotic resistance is a huge problem, contributing to nearly 1.27 million deaths worldwide in 2019. But antibiotic tolerance is a covert threat that researchers have only recently begun to explore.
Antibiotic tolerance happens when a bacterium manages to survive for a long time after being exposed to an antibiotic. While antibiotic-resistant bacteria flourish even in the presence of an antibiotic, tolerant bacteria often exist in a dormant state, neither growing nor dying but putting up with the antibiotic until they can “reawaken” once the stress is gone. Tolerance has been linked to the spread of antibiotic resistance.
I am a microbiologist who studies antibiotic tolerance, and I seek to uncover what triggers tolerant bacteria to enter a protective dormant slumber. By understanding why bacteria have the ability to become tolerant, researchers hope to develop ways to avoid the spread of this ability. The exact mechanism that sets tolerance apart from resistance has been unclear. But one possible answer may reside in a process that has been overlooked for decades: how bacteria create their energy.
Many antibiotics are designed to break through the bacteria’s outer defenses like a cannonball through a stone fortress. Resistant bacteria are immune to the cannonball because they can either destroy it before it damages their outer wall or change their own walls to be able to withstand the impact.
Tolerant bacteria can remove their wall entirely and avoid damage altogether. No wall, no target for the cannonball to smash. If the threat goes away before too long, the bacterium can rebuild its wall to protect it from other environmental dangers and resume normal functions. However, it is still unknown how bacteria know the antibiotic threat is gone, and what exactly triggers their reawakening.
My colleagues and I at the Dörr Lab at Cornell University are trying to understand processes of activation and reawakening in the tolerant bacteria responsible for cholera, Vibrio cholerae. Vibrio is rapidly evolving resistance against various types of antibiotics, and doctors are concerned. As of 2010, Vibrio is already resistant to 36 different antibiotics, and this number is expected to continue rising.
To study how Vibrio develops resistance, we chose a strain that is tolerant to a class of antibiotics called beta-lactams. Beta-lactams are the cannonball sent to destroy the bacteria’s fortress, and Vibrio adapts by activating two genes that temporarily remove its cell wall. I witnessed this phenomenon using a microscope. After removing its cell wall, the bacteria activate even more genes that morph it into fragile globs that can survive the effects of the antibiotic. Once the antibiotic is removed or degraded, Vibrio returns to its normal rod shape and continues to grow.
In people, this process of tolerance is seen when a doctor prescribes an antibiotic, typically doxycycline, to a patient infected with cholera. The antibiotic temporarily seems to stop the infection. But then the symptoms start back up again because the antibiotics never fully cleared the bacteria in the first place.
The ability to revert back to normal and grow after the antibiotic is gone is the key to tolerant survival. Exposing Vibrio to an antibiotic for a long enough time would eventually kill it. But a standard course of antibiotics often isn’t long enough to get rid of all the bacteria even in their fragile state.
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