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(Photo-)Control of Persisters: Targeting the Magic Spot

Project description

Persistence is not always a desirable trait

Persistence in the face of adversity is often rewarded with victory over obstacles; unfortunately for us, this is also true for many bacteria under attack by antibiotics. While much attention is given to antimicrobial resistance, so-called persistence is an equally challenging public health problem. Bacterial persisters that can revive after antibiotic treatment stops have an important pathway mediating the ‘stringent response’ that is not seen in mammals. Despite significant research into this ubiquitous pathway in bacteria, enhanced knowledge has so far not been translated into biochemical approaches to modulate it and combat the inefficacy of some antibiotics. The EU-funded PP-MAGIC project is investigating the molecular mechanisms of the stringent response with a goal of inhibiting it with light. Insight could lead to novel therapies against this subgroup of bacteria, minimising the occurrence of chronic bacterial infections.

Objective

The abusive use of antibiotics has led to multidrug-resistant bacteria and the acute threat of a post-antibiotic era. However, apart from resisters, there is a subgroup of bacteria called persisters that surviveby recalcitrance to antibiotic treatment. Persisters are not resistant to antibiotics but simply survive by metabolic shutdown. Upon withdrawal of antibiotics, these persisters resuscitate and regenerate the colony. They are heavily involved in failure of antibiotic treatment and the development of chronic infections. Bacterial persistence is controlled by the stringent response, which itself is mediated by hyperphosphorylated nucleotides, known as the magic spot (MS) nucleotides or (p)ppGpp. The importance of the stringent response, its omnipresence in the domain of bacteria, its connection to persister formation and tolerance to (antibiotic) stress, and its absence in mammals has led to significant research in microbiology. However, until recently these activities have not been paralleled by the development of chemical biology approaches. The current proposal aims to fill this gap by research into
(1) synthetic methodology targeting the magic spot nucleotides and their analogs,
(2) tools to identify target proteins of (p)ppGpp, and more generally (p)ppNpp
(3) analytical approaches to extract, resolve, and quantify (p)ppGpp,
(4) strategies to control the stringent response and persister formation with light
(5) inhibitors of the stringent response.
These new tools will enable a detailed understanding of the stringent response and thus ultimately help in the design of new antibiotics effective against persisters. The goal is to develop methods to force bacteria into the persistent state or inversely wake them up by using light and small molecules. Forcing bacteria out of persistence and blocking their entry into this state in combination with antibiotic treatment is a highly promising strategy to avoid the development of chronic bacterial infections.

Host institution

ALBERT-LUDWIGS-UNIVERSITAET FREIBURG
Net EU contribution
€ 2 000 000,00
Address
FAHNENBERGPLATZ
79098 Freiburg
Germany

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Region
Baden-Württemberg Freiburg Freiburg im Breisgau, Stadtkreis
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 000 000,00

Beneficiaries (1)