New VIB research concludes that antibiotic tolerance in bacteria leads to genetic resistance

22 January 2019
A study conducted at the VIB-KU Leuven Center for Microbiology supports the theory that in bacteria, the strategy of generating ‘sleeping’ persister cells to survive antibiotic treatment drives the evolution of highly resistant strains. The findings indicate that therapeutic strategies combatting the emergence of persister cells are crucial to fighting antibiotic treatment failure, which claims 50,000 lives every year in the US and Europe. The results of the study are published in The ISME Journal, a Nature publication.

Bacteria use two different strategies to survive antibiotic treatment: resistance, or a general ability to grow in the presence of antibiotics, and tolerance, the formation of small numbers of antibiotic-tolerant ‘persister’ cells. These persister cells serve as a reservoir that can continue to cause disease. Research has shown that the type and schedule of treatment determines which strategy bacteria use to combat the effects of an antibiotic drug. Continuous low doses of antibiotics tend to incite general resistance, while intermittent high-dose treatment causes increased tolerance and persistence.

Two different survival strategies
Etthel Windels and colleagues in the group of Jan Michiels found that when bacteria create tolerant persister cells to survive intermittent high doses of antibiotic drugs, these persisters are more likely to generate genetic mutants that are even more antibiotic resistant than the original bacterial population.

Etthel Windels (VIB-KU Leuven Center for Microbiology): “This increased tolerance and persistence strategy was demonstrated by earlier experiments to act as a stepping stone towards the evolution of genetic resistance. This is because persister cells can produce new cells that are all genetically drug resistant. As a result, tolerance is the culprit behind many chronic and recurring infections. Our observations highlight the fact that tolerance is an important target for therapeutic strategies, as its genetic consequences are far-reaching.”

Linking drug resistance in bacteria and cancer cells
Despite recent research underlining the relevance of tolerance, doctors rarely take it into account when prescribing antibiotic regimens. Because the tolerance and persistence strategy has been documented in all major bacterial pathogens, discounting tolerance could potentially lead to the emergence of deadly genetically resistant strains.

Prof. Jan Michiels (VIB-KU Leuven Center for Microbiology): “Our study suggests that the link between tolerance and the emergence of resistance is widespread. Even more, there are marked similarities between this strategy in bacteria and drug resistance in cancer cell populations. As a result, new insights in these two fields may be complementary.”

Preventing cells from ‘falling asleep’
Earlier work by Dorien Wilmaerts, also from the Jan Michiels Lab, published in mBio, revealed important insights into the mechanisms driving resistance and persistence in bacteria.

Dorien Wilmaerts (VIB-KU Leuven Center for Microbiology): “Our research also focused on bacterial persister cells, which go into a sort of protected hibernation mode in order to survive antibiotic drugs. We investigated the mechanisms behind how these cells fall into this deep sleep and thus avoid being killed, potentially leading to new ways of preventing the formation of persister cells.”


Publication
Bacterial persistence promotes the evolution of antibiotic resistance by increasing survival and mutation rates, Windels, Michiels et al., The ISME Journal, 2019

The persistence-inducing toxin HokB forms dynamic pores that cause ATP leakage, Wilmaerts et al., mBio, 2018

Questions from patients
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Research


Etthel Windels, Jan Michiels, Joran Michiels en Dorien Wilmaerts



Jan Michiels
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