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A new way of fighting bacteria?

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Microbiologists at the University of Geneva (UNIGE), Switzerland, studied the toxin-antitoxin system HigBA, which can be found in many pathogenic and non-pathogenic bacteria, and found a novel regulatory mechanism with potential implications on how to fight bacterial infection. The NCCR Chemical Biology is particularly excited about this new publication as the significant financial and logistics support it offered to Dr. Kirkpatrick and Prof. Viollier group leaded to a relevant finding.

In bacteria, toxin-antitoxin systems consist of a set of two closely linked genes. Situated on the same chromosome, they encode both a protein ‘poison’ and a counteracting ‘antidote’. Under normal conditions, the antitoxin protein fixes on the toxin protein and prevents it from acting. But in response to environmental stress, the antitoxin proteins are broken down, which allows the toxins to poison the cells. Microbiologists at the University of Geneva (UNIGE), Switzerland, studied the toxin-antitoxin system HigBA, which can be found in many pathogenic and non-pathogenic bacteria, and found a novel regulatory mechanism. When acting on the toxin, this mechanism works like a “suicide button” that kills the cell. This discovery could open the doors to potential new treatments of bacterial infections. The results can be read in Nature Microbiology.

Fighting bacteria with their own weapons

In most cases, it is impossible to artificially inactivate the antitoxin gene. But thanks to the unique mechanism of gene regulation in this system, the UNIGE scientists managed to do so. Indeed, HigBA is regulated in a very unusual way. Gene expression is regulated by DNA binding proteins known as “transcription factors”, which can either activate or repress gene expression. In the family of toxin-antitoxin systems to which HigBA belongs, the antitoxin is also a repressive transcription factor, which prevents the toxin and antitoxin genes from being expressed. Typically, the antitoxin is the only transcription factor that regulates toxin and antitoxin expression. The HigBA system, however, is also regulated by a DNA damage-responding transcription factor, capable of much more strict repression than the antitoxin. This regulation is what permits the mutation of the antitoxin gene: instead of responding to general stress, it only responds to DNA damage stress. “Unexpectedly, we found that HigBA acts like a highly specific «suicide button» for when the bacteria are suffering from DNA damage, such as can be caused by antibiotics”, adds Clare Kirkpatrick. HigBA toxin-antitoxin system can be found in many bacteria. This very specific mechanism is most probably largely present, too. Knowing this, strategies to activate or block the toxin can be imagined. “Our discovery can change the way we fight bacterial infection. Instead of using chemical warfare, i.e. antibiotics, we could force bacteria to turn their weapons on themselves,” concludes Patrick Viollier.

The NCCR Chemical Biology funded the chemical screening campaign for this project performed within the realm of ACCESS « Academic chemical screening platform for Switzerland », either at the EPFL (BSF-ACCESS) or at the University of Geneva (ACCESS GENEVA). This sponsorship followed its selection from the 1st call for screening proposals launched at the end of 2013. In addition to the financial support, the active contribution of ACCESS members throughout the project has been critical for designing, validating, performing and analyzing the data obtained with the screening assays. A collection of 1280 known drugs were used which included about 13% of known antibacterials. These came from the 100’000 compounds comprising the Chemical Collections stored at BSF-ACCESS. As a result, Clare Kirkpatrick detected five antibiotics not previously known to interact with the pathway studied in this publication and validated their inhibitory properties. A critical part of the study came when focusing on two of the five molecules, belonging to the chemical family of quinolones, revealed by the screens. It was then possible, as a major novel finding, to confirm the strict DNA damage-dependence of the toxin-antitoxin system and show that this system is active when exposed to real DNA damaging antibiotics that are used in a clinical setting.

Written by Victoria Monti (UNIGE, CMU)

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