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Interrogating the diversity of gut colonization strategies in multidrug-resistant E. coli to deduce robust competitive exclusion-based treatments

Project description

Competing for the same niche: a new strategy against antibiotic resistance

Many bacteria such as Escherichia coli evolve mechanisms to fight the effect of antibiotics. An example of such a strategy is the expression of extended-spectrum beta-lactamases (ESBLs), enzymes that break down penicillin and cephalosporins, rendering them ineffective against infections. To contribute to the development of new treatments, the EU-funded ECOSTRAT project proposes to study the evolution of ESBL-producing E. coli. Researchers will investigate the colonisation of the mammalian gut by ESBL E. coli to identify determinant factors and genes. Results will lay the foundation for novel treatments that rely on the competition with other microbiota.

Objective

The rise of multidrug-resistant bacteria limits the options to treat critically ill patients. In 2015, Escherichia coli producing Extended Spectrum β-Lactamases (ESBL) were the leading cause of death attributable to antibiotic resistant bacteria in Europe. The failure to address these infections using standard antibiotherapy calls for better understanding of how these bacteria evolve in order to develop new treatments.
Presence of resistance and virulence genes correlates with high prevalence in ESBL clones. Since the intestinal tract of mammals represents a major ecological niche for E. coli, gut colonization ability must have predisposed certain clones to evolutionary success during the antibiotic era. In particular, competition against the gut microbiota should select for colonization factors that predate the acquisition of resistance.
To test this hypothesis, we will compare strategies for gut colonization in ESBL clones of different prevalence in absence of antibiotics. Using mice, we will be able to modulate selective pressures exerted by the intestinal microbiota. We will compare gut colonization factors in ESBL clones by performing parallel high-throughput genetic screening in conventional mice (aim 1). We will analyze adaptability and the stability of resistance and virulence genes during long-term colonization (aim 2). Subsequent competitions in gnotobiotic mice harboring permissive microbiota will allow us to deduce functions needed for colonization in the presence of a competitive microbiota. In aim 3, we will measure the impact of competitors transmitted from cohabitant to infected mice on the duration of ESBL E. coli carriage and assess potential synergies with the adaptive immunity in vaccinated hosts.
Overall, we will unravel with unprecedented depth the general principles of intestinal colonization in ESBL E. coli, shed new light on the global success of prevalent clones and conceptualize robust antibiotic-free competition-based treatments.

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Topic(s)

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Funding Scheme

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ERC-COG - Consolidator Grant

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Call for proposal

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(opens in new window) ERC-2020-COG

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Host institution

UNIVERSITAT BASEL
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 993 191,00
Address
PETERSPLATZ 1
4051 Basel
Switzerland

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Region
Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 993 191,00

Beneficiaries (1)

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