Have you ever had a nasty infection that just won’t go away? Or a runny nose that keeps coming back? You may have been dealing with a bacteria that is tolerant to, but not yet resistant to, antibiotics.
Antibiotic resistance is a huge problem, which is being contributed to nearly 1.27 million deaths worldwide in 2019. But antibiotic tolerance is a secret threat that researchers have only recently begun to investigate.
Antibiotic tolerance happens when a bacteria manages to survive for a long time after being exposed to an antibiotic. While antibiotic resistant bacteria thrive even in the presence of an antibiotic, tolerant bacteria often live in a dormant state, neither growing nor dying, but tolerate the antibiotic until they can “wake up” once the stress is gone. tolerance has been linked to the spread of antibiotic resistance.
I’m a microbiologist who studies antibiotic tolerance, and I’m trying to discover what prompts tolerant bacteria to enter protective dormant sleep. By understanding why bacteria have the ability to become tolerant, researchers hope to develop ways to prevent the spread of this ability. The exact mechanism that distinguishes tolerance from resistance is unclear. But a possible answer may lie in a process that has been overlooked for decades: how bacteria create their energy.
Cholera and antibiotic tolerance
Many antibiotics are designed to break through the outer defenses of the bacteria like a cannonball through a stone fortress. Resistant bacteria are immune to the cannonball because they can destroy it before it damages their outer wall or alter their own walls to withstand the impact.
Tolerant bacteria can completely remove their wall and prevent damage altogether. No wall, no target for the cannonball to destroy. If the threat quickly disappears, the bacteria can rebuild its wall to protect it from other environmental hazards and resume its normal functions. However, it is still unknown how bacteria know that the threat of antibiotics is gone and what exactly triggers their awakening.
My colleagues and I at the Dorr Lab at Cornell University try to understand processes of activation and awakening in the tolerant bacteria responsible for cholera, Vibrio cholerae. vibration is rapidly evolving resistance against various types of antibiotics, and doctors are concerned. As of 2010, vibration is already resistant to 36 different antibioticsand this number is expected to continue to rise.
To study how vibration 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 vibration adapts by activating two genes that temporarily remove its cell wall. I witnessed this phenomenon using a microscope. After the cell wall is removed, the bacteria activate even more genes that turn it into fragile blobs that can survive the effects of the antibiotic. Once the antibiotic is removed or broken down, vibration returns to its normal rod shape and continues to grow.
In humans, this tolerance process is seen when a doctor prescribes an antibiotic, usually doxycycline, to a patient infected with cholera. The antibiotic seems to temporarily stop the infection. But then the symptoms come back because the antibiotics never completely cleared the bacteria in the first place.
The ability to return to normal and grow after the antibiotic wears off is key to permissive survival. naked vibration to an antibiotic that lasts long enough would eventually kill it. But a standard course of antibiotics is often not long enough to get rid of all the bacteria, even in their fragile state.
However, taking a medicine for a long time can damage healthy bacteria and cells, leading to even more discomfort and illness. Additionally, abuse and prolonged exposure Antibiotics can increase the chance that other bacteria in the body will become resistant.
Other bacteria develop tolerance
vibration is not the only species that shows tolerance. Researchers have even recently identified many infectious bacteria that have developed tolerance. Called a family of bacteria Enterobacteriaceaeincluding major foodborne pathogens Salmonella, Shigella And E coliare just a few of the many types of bacteria capable of antibiotic tolerance.
Since each bacteria is unique, the way tolerance develops seems to be too. Some bacteria, such as vibration, erase their cell walls. Others can change their energy sources, increase their ability to move or simply pump them out the antibiotic.
I recently discovered that one metabolism of bacteria, or the way it breaks down “food” to make energy, may play an important role in its ability to become tolerant. Different structures within a bacterium, including the outer wall, are made of specific building blocks such as proteins. Stopping the bacteria’s ability to make these pieces weakens the wall, making it more likely to take damage from the outside before it can bring the wall down.
Tolerance and resistance are interrelated
While much research has been done on how bacteria develop tolerance, an important piece of the puzzle that has been neglected is how tolerance leads to resistance.
In 2016, researchers discovered how making bacteria tolerant in the laboratory. After repeated exposure to various antibiotics, E coli cells could adapt and survive. DNA, the genetic material that contains instructions for cell function, is a fragile molecule. When DNA is quickly damaged by stress, such as antibiotic exposure, the cell’s repair mechanisms tend to go haywire and cause mutations that can create resistance and tolerance. Because E coli is similar to many different types of bacteria, these researchers’ findings revealed that, ironically, essentially any bacteria can develop tolerance if pushed to its limits by the antibiotics intended to kill them.
Another important recent discovery was that the longer bacteria remain tolerant, the more likely they are to do so develop mutations that lead to resistance. Tolerance allows bacteria to develop a resistance mutation that reduces their chance of being killed during antibiotic treatment. This is especially relevant for bacterial communities commonly seen in biofilms that tend to coat high-touch surfaces in hospitals. Biofilms are slimy layers of bacteria that secrete a protective jelly that makes antibiotic treatment difficult and makes DNA sharing between microbes easy. They can encourage bacteria to develop resistance. These conditions are believed to resemble what might happen during antibiotic-treated infections, where many bacteria coexist and share DNA.
Researchers are calling for more research into antibiotic tolerance in the hope that this will lead more robust treatments in infectious diseases and cancers. And there is reason to be hopeful. In a promising development, a mouse study found that decreasing tolerance also reduced resistance.
Meanwhile, there are steps everyone can take to help fight antibiotic tolerance and resistance. You can do this by taking an antibiotic exactly as prescribed by a doctor and emptying the entire bottle. Brief, inconsistent exposure to a drug encourages bacteria to become tolerant and eventually resistant. Smarter use of antibiotics by everyone can halt the evolution of tolerant bacteria.
