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Disentangling the stringent response to engineer novel anti-persister drugs

Project description

Novel mechanistic insight into antibiotic resistance

Antibiotic-resistant bacteria are a growing health concern worldwide with many healthcare implications. Emerging evidence indicates that dormant bacteria subpopulations which are difficult to eradicate with conventional means are the primary source of antibiotic resistance. The EU-funded DiStRes project is investigating the RelA/SpoT (RSH) proteins that promote the stringent response in bacteria and modulate cell metabolism through the (p)ppGpp. Through a combined microbiology and structural biology approach, researchers will focus on the molecular mechanisms of ppGpp synthesis and hydrolysis. DiStRes will not only shed light on the mechanism of drug resistance, but also help design and screen novel drug candidates that target the stringent response in persistent bacteria.

Objective

Bacterial “superbugs”, refringent to antibiotic treatments, have rapidly increased with the turn of the century. Slow growing, dormant cells (known as persisters) are subpopulations of bacteria that tolerate antibiotics and are considered a primary source of infections for antibiotic-resistant pathogens since they are difficult to eradicate in conventional ways. Mutations in RelA/SpoT (RSH), the effectors of the stringent response, promote antibiotic tolerance and persistent infections and are commonly selected in clinical settings of a variety of pathogens. However, despite the importance of the RSH-mediated stringent response, there is no comprehensive knowledge on the inner workings of the enzymes, or drugs that modulate the bacterial response to stress. Modern structurally biology is currently in the midst of a revolution comparable to that of the Genomic breakthrough of the end last century. This has facilitated access to structural information and increased the accuracy of the modeling and design of de novo structures of proteins and small molecules. Thus my overarching goal is to target key steps in the molecular mechanisms of ppGpp synthesis and hydrolysis catalysed by RSH enzymes, to discover active compounds against persisters. The highlight of this proposal is a new system biology approach that combines cellular microbiology (at a single cell resolution) with structural engineering, biophysical, biochemical and chemical-biology methods to design, screen and validate novel small molecule drug candidates targeting the stringent response. Based on preliminary keystone results from my group, we devised a proof of concept experiment for which we designed a catalogue of novel modulators of the stringent response customized to target bacteria in a specific or broad spectrum way. The success of this exercise guarantees this strategy will not only deliver new antipersister compounds and biotech tools, but will also impinge fundamental research in microbiology.

Host institution

UNIVERSITE LIBRE DE BRUXELLES
Net EU contribution
€ 2 000 000,00
Address
AVENUE FRANKLIN ROOSEVELT 50
1050 Bruxelles / Brussel
Belgium

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Region
Région de Bruxelles-Capitale/Brussels Hoofdstedelijk Gewest Région de Bruxelles-Capitale/ Brussels Hoofdstedelijk Gewest Arr. de Bruxelles-Capitale/Arr. Brussel-Hoofdstad
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 000 000,00

Beneficiaries (1)