18 May 2024
Job Information
- Organisation/Company
Université de Strasbourg- Research Field
Engineering
Biological sciences » Biology
Computer science » Informatics- Researcher Profile
Recognised Researcher (R2)
Leading Researcher (R4)
First Stage Researcher (R1)
Established Researcher (R3)- Country
France- Application Deadline
30 Jun 2024 - 22:00 (UTC)- Type of Contract
Temporary- Job Status
Full-time- Offer Starting Date
1 Oct 2024- Is the job funded through the EU Research Framework Programme?
Not funded by an EU programme- Is the Job related to staff position within a Research Infrastructure?
No
Offer Description
Among the challenges of modern medicine, the discovery of new drugs to fight against multi-resistant pathogens constitutes a priority emergency. The World Health Organization (WHO) says the situation is particularly critical for multidrug-resistant Gram-negative bacteria such as Pseudomonas, Acinetobacter and certain enterobacteria. These bacteria are intrinsically resistant to many antibiotics due to the low permeability of their membrane. Increasing this permeability therefore constitutes an important challenge which, if successful, could open the way to innovative therapeutic approaches against multi-resistant bacterial infections.
Although very impermeable, the bacterial membrane has existing cross-membrane transport pathways dedicated for the uptake of nutrients. Hijacking these nutrient absorption pathways with nutrient-antibiotic conjugates, the so-called Trojan horse strategy, can significantly improve the uptake of potential antibiotics by bacteria. Among all nutrients, iron is very promising since this metal is involved in many crucial biological processes1 and cannot be replaced by any alternative molecule. Bacteria excrete chelators called siderophores to access iron. Siderophores are synthesized by bacteria, then released into the bacteria's environment where they scavenge iron very efficiently and bring it back to the bacteria via specific transporters2 . The idea of the Trojan horse strategy is to covalently link an antibiotic to a siderophore, so if the bacteria ingests the siderophore, it also ingests the bound antibiotic3 . Cefiderocol, a siderophore-antibiotic conjugate developed by Shionogi, was recently approved (April 2020) by the European Medicine Agency in the treatment of infections caused by Gram-negative bacteria, demonstrating the effectiveness of Trojan horse-type strategies4 .
The development of such a therapy requires excellent knowledge of the different pathways allowing microorganisms to access iron. Indeed, if the antibiotic is coupled with a siderophore that is not used by the bacteria in its current environment, the vectorization will be ineffective. However, there are numerous absorption pathways in Pseudomonas aeruginosa. Based on current knowledge, this bacterium has 15 different iron absorption strategies5 including:
- a ferrous iron (Fe2+) absorption pathway
- three routes of heme acquisition
- at least two pathways for acquiring ferric iron (Fe3+) using the two main siderophores produced by the bacteria itself (pyoverdine and pyochelin)
- at least 10 different strategies known as “hacking exogenous siderophores” (or exosiderophores, i.e. siderophores produced by other bacteria) to absorb Fe3+.
Indeed, in multi-species communities and during infections, most bacteria can use siderophores produced by other bacteria by expressing compatible transporters capable of capturing and iron in complex with siderophores that they cannot not synthesize themselves6 . It is considered that absorption pathways are generally expressed at a basal level and pathogens will only induce the expression of the most efficient iron acquisition pathway(s) depending on the bacterial environment or for example the type of iron.
It has also been shown that bacteria are often capable of detecting the presence of siderophores or exosiderophores and expressing the corresponding transporter, which then allows them to access iron7-8 . As part of a preliminary study, the team of Dr. Isabelle Schalk (UMR7242, Illkirch) showed that bacteria are also capable of detecting the presence of siderophores even if they are coupled with an antibiotic and of expressing the corresponding acquisition pathway. Furthermore, as part of a previous thesis co-directed by Dr. Isabelle Schalk and Morgan Madec, it was demonstrated that for each iron import route in P. aeruginosa, the concentration of siderophore necessary for inducing its expression of the corresponding transporter is not the same. For example, in the case of iron import via enterobactin (exosiderophore produced by E. coli), the expression of the corresponding pathway starts from an exosiderophore concentration of 100 nM and reaches its maximum at approximately 3 µM. In the case of nocardamine (the exosiderophore produced by a fungus), the expression of the corresponding pathway begins at a concentration of 1uM and does not reach its maximum even at the highest experimentally accessible concentration (100 µM). These data clearly illustrate that each pathway has its own regulatory pattern and that its expression adjusts to the type of siderophore or exosiderophore present and their concentrations. The question of how bacteria select, optimize and synchronize the expression of their different transport pathways in response to the external environment remains unknown. Likewise, the dynamics of these phenotypic changes are completely unknown. Answering these questions will have a very important impact on the development of effective antibiotic vectorization strategies based on siderophores.
Given this context, the thesis project includes two main objectives and is part of a larger project funded by an ANR (IRUPP 2023-32027) including, among others, the 3 work packages described below. The two main goals of this thesis are:
1. The study, at the single cell level, of the dynamics associated with the expression of iron absorption pathways under selected and relevant conditions identified from the results of the first part, as well as the measurement heterogeneity in the behavior of bacteria within the same population.
2. The implementation of a mathematical model of the biological system (the acquisition of iron by P. aeruginosa according to its environment) which acts as a common thread throughout the thesis work. This work will be based on biological data provided by I’s laboratory. Schalk, coordinator of the ANR IRUPP).
Funding category: Autre financement public
Bourse de la Fondation Jean-Marie Lehl
PHD title: Doctorat en Sciences de la vie et Santé / Doctorat en Sciences de l'Ingéieur (selon le profil))
PHD Country: France
Requirements
Specific Requirements
The phD topic is at the interface between engineering sciences (and more specifically the design of instrumental microsystems) and biology. Thus the candidate should have a very strong know-how in one of the two domain, and at some basic knowledge of the other. Any cases, minimal skills in computer sciences are also required.
Additional Information
Work Location(s)
- Number of offers available
- 1
- Company/Institute
- Université de Strasbourg
- Country
- France
- City
- Illkirch
- Geofield
Where to apply
- Website
https://www.abg.asso.fr/fr/candidatOffres/show/id_offre/123964
STATUS: EXPIRED