01 March 2022, Leuven, Belgium
Sleeping bacterial cells or persister cells contribute significantly to antibiotic resistance. The research team of Prof. Jan Michiels (VIB-KULeuven Center for Microbiology) found that the timing of waking up can be linked with the development of antibiotic resistance. Together with their recent discovery that sour bacteria become hyper tolerant, the team highlights potential new targets for more efficient antibiotic treatments.
A glitch of modern healthcare
Antibiotic resistance is on the rise and one of the leading causes of death worldwide, killing almost 3.500 people a day. Antibiotic-tolerant bacteria cells - called persister cells - are an important source of resistant bacteria. To protect the population from extinction, a small number of cells adopt an inactive or sleepy state which ensures their survival during antibiotic treatment. When persister cells exit this sleepy state in a drug-free environment, they continue to propagate and reinstate the infection. Reducing the application of antibiotics in human and veterinary medicine should slow the emergence of tolerant cells. But additionally, investments in the discovery and development of next-generation antibiotics, with a novel mode of action, impose themselves. Understanding the underlying mechanisms that catalyze antibiotic tolerance could allow for the development of novel therapies, that also target persister cells.
DNA damage repair pathway prone to mistakes
Over the past decades, persistence research has discovered multiple mechanisms that trigger persister state entry but how persisters exit their sleepy state, remained elusive. Persister awakening could nevertheless be an interesting target for anti-persister therapies. Synchronous exit from the sleepy state would efficiently eradicate persister cells from the bacterial colony, and so prevent the subsequent formation of resistant mutants. The research published today in Cell Reports, by Dr. Dorien Wilmaerts and colleagues, aims to identify the weak spot of persister cells. “During antibiotic treatment, persister cells build up DNA damage. The cells will, by default, repair this DNA damage during awakening, as it is essential for persister survival,” says Dr. Wilmaerts. “We demonstrate that the DNA damage repair underlies the timing of awakening and contributes to resistance.” Persister cells can repair DNA damage in multiple ways. Dr. Wilmaerts and co, found that one particular repair mechanism leads to a higher number of mutations, which in turn increases the risk to develop antibiotic resistance. “The repair mechanisms activated in persister cells are an interesting target for novel antibacterial drug discovery, as it would prevent the development of resistance towards existing treatments.”
Going sour to survive
Only a few weeks ago, the team of Prof. Michiels in collaboration with Prof. Matthias Heinemann (University of Groningen) published another important aspect of antibiotic tolerance in the leading journal Nature Communcations. “Successive rounds of antibiotic treatment in the lab led to the subsequent isolation of mutant bacteria that became hyper tolerant towards antibiotics,” says Dr. Bram Van den Bergh, the lead scientist. “These hyper tolerant cells suffer from a malfunctioning of their power plant, not only resulting in lower energy levels but also in significant acidification of the inside of the bacterial cell. But we didn’t fully understand how the dots were connected”. Until they met Prof. Heinemann at a conference, who observed similar acidification of the cell in extremely tolerant bacteria. “That is when we decided to join forces,” Prof. Heinemann says. “Together we found that the acidification shuts down the main target of the antibiotics that we used, which is the protein production machinery. Acidification typically indicates an imbalance of metabolism and causes a stress response, but in bacteria, it is also the path to antibiotic survival.”
Multiple approaches to defeat bacterial resistance
Since the discovery of penicillin in 1928 by Prof. Alexander Fleming, antibiotics have become an important part of modern healthcare. But excessive use has driven the evolution of resistant bacteria. To safeguard the merit of antibiotic treatments in human disease control, efforts have to be made to slow down the progression of bacterial resistance. “Our recent work provides unique insights into the mechanisms contributing to antibiotic tolerance. Counteracting the bacteria to become sour could be a standardized manner to improve existing antibiotic treatments,” Prof. Michiels clarifies. “But it doesn’t stop there. Next-generation antibiotics should complement our strategy to compete and defeat tolerant bacteria. Now that we understand how to wake the sleeping bacteria, the long-awaited anti-persister therapies seem within reach.”
Wilmaerts et. al., Cell Reports (2022)
Van den Bergh et. al., Nature Communications (2022)
The work of Wilmaerts et. al. was supported by the Fund for Scientific Research Flanders (FWO), KU Leuven and VIB
The work of Van den Bergh et. al. was supported by grants from the Fund for Scientific Research Flanders (FWO), the Dutch Research Council (NWO), the Deutsche Forschungsgemeinschaft, the Federation of European Microbiological Societies (FEMS), the Belgian American Educational Foundation (BAEF), the European Molecular Biology Organization (EMBO), the Agency for Innovation by Science and Technology (IWT), KU Leuven and VIB
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VIB-KU Leuven Center for Microbiology
The big impact of bacteria on our health, the use of yeasts to enhance the production of chocolate, beer or bioethanol, yeast as a model system for studying human disease ... these are just a few of the research areas for the scientists at the VIB-KU Leuven Center for Microbiology. Their research also has important implications in various fields of application.
Basic research in life sciences is VIB’s raison d’être. VIB is an independent research institute where some 1,500 top scientists from Belgium and abroad conduct pioneering basic research. As such, they are pushing the boundaries of what we know about molecular mechanisms and how they rule living organisms such as human beings, animals, plants and microorganisms. Based on a close partnership with five Flemish universities – Ghent University, KU Leuven, University of Antwerp, Vrije Universiteit Brussel and Hasselt University – and supported by a solid funding program, VIB unites the expertise of all its collaborators and research groups in a single institute. VIB’s technology transfer activities translate research results into concrete benefits for society such as new diagnostics and therapies and agricultural innovations. These applications are often developed by young start-ups from VIB or through collaborations with other companies. This also leads to additional employment and bridges the gap between scientific research and entrepreneurship. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information. More info can be found on www.vib.be.
KU Leuven is Europe’s most innovative university (Reuters) and ranks 45th in the Times Higher Education World University Rankings. As Belgium's largest university, KU Leuven welcomes 60,000 students from over 140 countries. Its 7,000 researchers are active in a comprehensive range of disciplines. KU Leuven is a founding member of the League of European Research Universities (LERU) and has a strong European and international orientation. University Hospitals Leuven, its network of research hospitals, provides high-quality healthcare and develops new therapeutic and diagnostic insights with an emphasis on translational research. More info: www.kuleuven.be/english.
University of Groningen
The Rijksuniversiteit Groningen is a research university with 11 faculties, a global outlook, deeply rooted in Groningen and also located in Leeuwarden. The University is in the top 100 of important ranking lists. It is very popular with its 35,000 students and 6,500 staff members. They are challenged to excel, burgeoning talent is cultivated and the keyword is quality. The UG is committed to actively cooperating with its partners in society, with a special focus on its research themes Healthy Ageing, Energy and Sustainable Society.