When bacteria are under energy stress – burning more energy than they produce, it increases their chances of developing antibiotic resistance. A new study offers new insight into how antibiotic resistance develops – and how we might stop it.
Antimicrobial resistance is one of the greatest global health crises.
When bacteria survive antibiotic treatment, even common infections can become deadly – and this is already happening on a large scale. Worldwide, more than 1.3 million people die per year because of infections that used to be treatable with antibiotics but are not today.
Now, new research shows that antibiotics not only kill bacteria but can also stress them so much that they more easily develop resistance.
The discovery could pave the way for new drugs that prevent bacteria from developing resistance to improve confidence that an antibiotic will cure an infection without causing relapse in the future.
“We believe that this discovery could lead to better antibiotic treatments. First, we can think about developing treatments that do not affect the bacterial mechanisms involved in developing resistance as much, and second, we can develop drugs that directly target the mechanisms so that bacteria develop resistance more slowly or not at all,” explains a researcher behind the study, Jason Yang, Assistant Professor, Department of Microbiology, Biochemistry and Molecular Genetics and Center for Emerging and Re-emerging Pathogens at Rutgers New Jersey Medical School, Newark, USA.
Some antibiotics stress bacteria more than others
The researchers aimed to understand the role of bacterial metabolism in developing antibiotic resistance. They therefore investigated how bacterial metabolism changes during antibiotic treatment.
Before this research, it was already known that antibiotics can have different effects on bacterial metabolism. Some antibiotics slow bacterial metabolism, and others ramp it up.
Those that increase bacterial metabolism often kill the bacteria, whereas those that decrease bacterial metabolism prevent them from growing which allow bacteria to better survive antibiotic treatment.
The researchers treated Escherichia coli bacteria with ciprofloxacin – an antibiotic used to treat conditions such as travellers’ diarrhoea – to determine how it affects the bacteria’s metabolism and ability to develop resistance.
“We know that metabolism plays an important role in developing antibiotic resistance, but the specific mechanisms are still poorly understood,” says Jason Yang.
Stress causes bacteria to use more energy
Through various experiments, the researchers showed that treatment with ciprofloxacin metabolically stressed the E. coli cells, and their energy demand exceeded their energy production.
They found that the E. coli cells were burning more energy than they could make – and their system broke down.
The researchers then engineered bacteria that constantly lacked energy – to determine how this affected the development of resistance. The aim was to see what this meant for the development of antibiotic resistance.
When bacteria are running low on energy, they try to compensate by cranking up their metabolism. Like a bathtub without a plug: you have to turn up the tap to keep the water level from dropping.
When bacteria use more energy, their genes can mutate more often – and some can make them resistant to antibiotics.
“We found that when bacteria get stressed and start burning substantial energy, they are harder to kill – and they evolve resistance faster,” notes Jason Yang.
Stressed bacteria mutate more rapidly than normal
Another discovery was that, under stress, bacteria act differently depending on their exposure to antibiotics. Some bacteria become dormant, whereas others ramp up their mutation rate – raising the risk of resistance.
“If antibiotics do not kill them all, the survivors may be those most likely to evolve resistance – precisely because they are stressed and burning through energy,” explains Jason Yang.
Jason Yang says that the discoveries have several promising implications.
First, the researchers obtained a key insight that opens the door to future studies.
Knowledge of bacterial stress responses can also be used outside of healthcare – for example in industry, in which bacteria are used to produce biofuels and chemicals.
“In this context, controlling the stress response of bacteria may help to control cell growth, which could benefit production yields in industry,” says Jason Yang.
Researchers aim to curb resistance by targeting stress
The greater potential lies in tackling antibiotic resistance itself.
In the future, scientists can investigate how to target the stress response of bacteria and thereby reduce the risk of developing resistance. Drugs might also target the stress response directly – just like antibiotics themselves.
“Our study shows that when bacteria are already low on energy, they switch on a mechanism that protects them from antibiotics. Therefore, we are very interested in finding substances that can prevent the energy level from dropping during treatment. If we can prevent stress, we may be able to make existing antibiotics work better – and keep resistance at bay for longer,” concludes Jason Yang.
The findings shift the way we think about bacterial stress – and point to new strategies for staying one step ahead of resistance.
