Waking up bacteria to overcome antibiotic resistance

Waking up bacteria to overcome antibiotic resistance

Targeting persister cells to combat antibiotic tolerant bacteria

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.”

Bram Van den Bergh, Jan Michiels and Dorien Wilmaerts
Bram Van den Bergh, Jan Michiels and Dorien Wilmaerts

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.”

 

Publications

Wilmaerts et. al., Cell Reports (2022)
https://doi.org/10.1016/j.celrep.2022.110427

Van den Bergh et. al., Nature Communications (2022)
10.1038/s41467-022-28141-x

 

Financing

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

Astrid Gadeyne
Astrid Gadeyne Science Communications, VIB

Note to the editor

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