New insights into a bacterial toxin–antitoxin system may lead to alternatives to antibiotics
The toxin she works with is so potent that it kills the bacteria that produce it
Antibiotics have transformed medicine. However, years of excessive and inappropriate use have led an increasing number of bacteria to develop resistance to these drugs. “Antibiotic resistance is one of the greatest health challenges of our time”, says researcher Yana Girardin of the Structural Biology Brussels research group (Faculty of Science and Bioengineering Sciences, VUB) in her doctoral thesis. “It may rightly be described as a silent pandemic. Bacteria are becoming progressively less susceptible to existing medicines, causing infections that were once easily treated to become life-threatening once again.” The search for alternative solutions in her opinion is crucial.
A promising avenue lies in so-called toxin–antitoxin (TA) systems, intrinsic mechanisms in bacteria composed of two components: on the one hand, a toxin capable of arresting bacterial growth or even killing the cell; on the other, an antitoxin that neutralises its effect. Girardin’s doctoral research focused on such a system in Vibrio cholerae, the bacterium responsible for cholera.
Central to her research were two proteins: the toxin VcParE2 and the antitoxin VcParD2. The toxin disables a crucial bacterial enzyme, DNA gyrase, which is a known target of certain antibiotics. “What is remarkable”, Girardin explains, “is that VcParE2 acts in a manner distinct from the antibiotics that are currently in use. This opens the door to an entirely new mechanism of action.”
In order to study the toxin and its antitoxin in detail, Girardin first had to overcome a practical obstacle: the toxin is so potent that it kills the bacteria that produce it, making it particularly difficult to generate in the laboratory. The search for a suitable method to produce the toxin yielded valuable approaches for working with toxic bacterial proteins. Girardin devised an ingenious system by which the toxin gene can be introduced into bacteria in a controlled manner, without causing their immediate death. This strategy also makes it possible to compare the toxicity of different toxins. In addition, she succeeded in producing sufficient quantities of the protein through alternative production methods, such as the use of insect cells. “That was truly a breakthrough”, she says, “as purifying the toxin on its own had never previously been achieved owing to its extreme toxicity.”
Her experiments identified the specific region of the toxin responsible for inhibiting DNA gyrase, and clarified how the antitoxin shields that site in order to prevent damage. In doing so, she not only characterised this specific system in Vibrio cholerae, but also contributed to a broader understanding of how TA systems function.
“Our research demonstrates how bacteria can restrain their own growth and how we may better comprehend that mechanism”, Girardin concludes, “and this knowledge may prove valuable in the search for new strategies to combat antibiotic resistance.”
Further information:
Yana Girardin: yana.andrea.girardin@vub.be
Exploring the interaction landscape of Vibrio cholerae toxin ParE2: Gyrase inhibition and neutralisation by ParD2
