Cystic fibrosis is a debilitating and inherited lung disease. Most people with the disease have a permanent bacterial lung infection – often deadly. Researchers have now revealed one of the bacteria’s possible defence systems. Bacteria can potentially poison themselves to go into standby mode and thereby survive antibiotics. By understanding the system, researchers may develop a new arsenal against bacterial infections.
Antibiotic resistance is one of the greatest threats to world health. The problem arises when small groups of bacteria survive treatment, and spread within and between patients. Now researchers are closer to understanding how bacteria can tolerate antibiotics. By analysing bacterial samples taken over 10 years from people with cystic fibrosis, the researchers discovered several genes that potentially help bacteria to tolerate treatment.
“We found several genes that likely comprise toxin-antitoxin systems in bacteria. Under stressful conditions bacteria may use these to poison themselves and go into a standby mode, where they can survive antibiotic treatment. They also contain antitoxins that they release when the danger has passed,” explains Sandra Breum Andersen, a postdoctoral fellow at the NYU Langone Medical Center, New York City, United States.
Although researchers have not yet tested the system in the laboratory, they already know from other bacteria that toxin-antitoxin systems are very important for antibiotic tolerance. And if these systems turn out to be functioning in the bacteria that cause cystic fibrosis, this may contribute to explaining why they are never entirely eradicated. When antibiotic treatment stops, their antitoxin kicks in and the bacteria wake up again.
Ideal conditions for bacteria
The bacteria investigated by the researchers were the otherwise normally harmless Pseudomonas aeruginosa, which cannot infect healthy individuals. People with cystic fibrosis, however, have a gene mutation that results in the transport of salt in and out of their body’s cells not functioning normally. This means that the secretion of the phlegm-producing glands becomes dry and viscous, and this environment is ideal for bacterial infections.
“Almost everyone with cystic fibrosis is infected with P. aeruginosa, and although antibiotics can reduce the eruption of bacteria, they nearly always re-emerge. We therefore decided to track the bacteria among the same people over several years to see how they developed.”
The researchers examined bacteria from 33 people with cystic fibrosis. By comparing the development of the bacteria over the years and across the bacterial strains, they found 26 potential toxin-antitoxin systems, four of which were especially interesting.
“Although many of the systems are present in suspected mobile elements, which are small DNA fragments that can be exchanged between bacteria, four of them are present in the core genome which is conserved in the bacterial strains of all 33 people. This suggests that these four systems may be very important.”
Struggle for control
The genes of the four bacterial toxin-antitoxin systems from the people with cystic fibrosis were also found in other bacteria. This suggests that these systems were originally mobile but that Pseudomonas has adopted and integrated these systems into their genetic repertoire.
“Research on toxin-antitoxin systems and how they are related to antibiotic tolerance is rapidly developing field. If we can somehow prevent this small group of bacteria from going into standby mode or perhaps can bring them out of standby mode again, we can use this in conjunction with traditional antibiotic treatment. This might enable us to effectively combat several of these bacteria again.”
Although cystic fibrosis is a rare disease, the new research results may be very significant in other contexts. In research terms, cystic fibrosis is also a model disease because it is a well-known and obvious example of a genetic mutation that affects many organs simultaneously. The new results are therefore only one step forward for the researchers.
“We are already examining these systems in greater detail, first to confirm through experiments that they are actually toxin-antitoxin systems. We would like to see whether the bacteria will get better at going into standby mode the longer they have been in a person’s lungs.”
The researchers also want to determine whether some of the genes for toxin-antitoxin systems are regulated up or down in connection with antibiotic treatment.
“If we can understand these things, we will potentially have knowledge that will enable us to more effectively combat bacterial infections that cannot currently be combated with antibiotics.”
”Diversity, prevalence, and longitudinal Occurrence of type II toxin-antitoxin Systems of Pseudomonas aeruginosa infecting cystic fibrosis lungs” has been published in Frontiers in Microbiology. In 2016, the Novo Nordisk Foundation awarded a Postdoctoral Fellowship for research abroad to Sandra Breum Andersen , a main author. Two authors, Søren Molin and Helle Krogh Johansen, are affiliated with the Novo Nordisk Foundation Center for Biosustainability.