Many infections, even those caused by antibiotic-sensitive bacteria, resist treatment. This paradox has vexed physicians for decades, and makes some infections impossible to cure.
A key cause of this resistance is that bacteria become starved for nutrients during infection. Starved bacteria resist killing by nearly every type of antibiotic, even ones they have never been exposed to before.
What produces starvation-induced antibiotic resistance, and how can it be overcome? In a paper appearing this week in Science, researchers report some surprising answers.
"Bacteria become starved when they exhaust nutrient supplies in the body, or if they live clustered together in groups know as biofilms," said the lead author of the paper, Dr. Dao Nguyen, an assistant professor of medicine at McGill University.
Biofilms are clusters of bacteria encased in a slimy coating, and can be found both in the natural environment as well as in human tissues where they cause disease. For example, biofilm bacteria grow in the scabs of chronic wounds, and the lungs of patients with cystic fibrosis. Bacteria in biofilms tolerate high levels of antibiotics without being killed."A chief cause of the resistance of biofilms is that bacteria on the outside of the clusters have the first shot at the nutrients that diffuse in," said Dr. Pradeep Singh, associate professor of medicine and microbiology at the University of Washington in Seattle, the senior author of the study. "This produces starvation of the bacteria inside clusters, and severe resistance to killing."
"While this idea is appealing, it presents a major dilemma," Nguyen noted. "Sensitizing starved bacteria to antibiotics could require stimulating their growth, and this could be dangerous during human infections."
Nguyen and Singh explored an alternative mechanism.
Microbiologists have long known that when bacteria sense that their nutrient supply is running low, they issue a chemical alarm signal. The alarm tells the bacteria to adjust their metabolism to prepare for starvation. Could this alarm also turn on functions that produce antibiotic resistance?
To test this idea, the team engineered bacteria in which the starvation alarm was inactivated, and then measured antibiotic resistance in experimental conditions in which bacteria were starved. To their amazement, bacteria unable to sense starvation were thousands of times more sensitive to killing than those that could, even though starvation arrested growth and the activity of antibiotic targets."That experiment was a turning point," Singh said. "It told us that the resistance of starved bacteria was an active response that could be blocked. It also indicated that starvation-induced protection only occurred if bacteria were aware that nutrients were running low."
The second question was about the mechanism of the effect. How does starvation sensing produce such profound antibiotic resistance?
Again, the results were surprising.
Instead of well-described resistance mechanisms, like pumps that expel antibiotics from bacterial cells, the researchers found that the bacteria's protective mechanism defended them against toxic forms of oxygen, called radicals. This mechanism jives with new findings showing that antibiotics kill by generating these toxic radicals.
The findings suggest new approaches to improve treatment for a wide range of infections.
"Discovering new antibiotics has been challenging," Nguyen said. "One way to improve infection treatment is to make the drugs we already have work better. Our experiments suggest that antibiotic efficacy could be increased by disrupting key bacterial functions that have no obvious connection to antibiotic activity."
The work also highlights the critical advantage of being able to sense environmental conditions, even for single-celled organisms like bacteria. Cells unaware of their starvation were not protected, even though they ran out of nutrients and stopped growth. This proves again that, even for bacteria, "what you don't know can hurt you."
The Burroughs Welcome Fund, the Cystic Fibrosis Foundation, the National Institutes of Health, and the Canadian Institutes for Health Research supported this research.
The results are contained in the Science article, "Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria."
In addition to Nguyen and Singh, the researchers on the study were Amruta Joshi-Datar, Elizabeth Bauerle, Karlyn Beer, and Richard Siehnel of the Departments of Medicine and of Microbiology at the UW, James Schafhauser of McGill University, Francois Lepine of INRS Armand Frappier in Canada, Oyebode Olakanmi and Bradley E. Britigan of the University of Cincinnati, and Yun Wang of Northwestern University.
Leila Gray | EurekAlert!
Tag it EASI – a new method for accurate protein analysis
19.06.2018 | Max-Planck-Institut für Biochemie
How to track and trace a protein: Nanosensors monitor intracellular deliveries
19.06.2018 | Universität Basel
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
19.06.2018 | Physics and Astronomy
19.06.2018 | Life Sciences
19.06.2018 | Physics and Astronomy