CE44 - Biochimie et chimie du vivant

IRon Uptake Pathways in Pseudomonas aeruginosa: phenotypic switches and mechanism of regulation – IRUPP

Submission summary

One of the bottlenecks in antibiotic development is the ability of the drugs to enter bacteria. Iron uptake pathways are considered as promising gates for the import of antibiotics into bacteria and a nice example is the Cefiderocol developed and commercialized by Shionogi. To access iron, an essential nutrient, bacteria synthesize siderophores, small organic iron chelators. Siderophores are released in the bacterial environment where they efficiently scavenge iron before being taken up again by bacteria. Antibiotics can be attached to siderophores. Consequently, when the pathogen takes up ferric siderophore, it also imports the antibiotic in a “Trojan horse” strategy.
Genomic data highlighted that most bacteria genome code for several iron uptake pathways. The opportunist pathogen Pseudomonas aeruginosa, our model in the present project, has in its genome between 20-25 different iron uptake pathways with most of them using siderophores produced by other bacteria (xenosiderophores).
In contrast to the large amount of genomic data generated by bacterial genome sequencing, almost no data are available concerning the phenotypic plasticity linked to the expression of iron-uptake pathways in bacteria and the development of siderophore-antibiotic conjugates suffers from a low knowledge on how bacteria adapt select, regulate, optimize and synchronize the expression of their different iron import pathways in response to environment stimuli like the presence of xenosiderophores.
For this purpose, we propose to:
- (i) investigate the plasticity of the expression of these different iron uptake pathways in different growth conditions (planktonic and biofilm growth conditions, co-cultures between P. aeruginosa and Staphylococcus aureus, as well as in a human airway epithelial cell infection assay) and in the presence of different combinations of xenosiderophores and siderophore-antibiotic conjugates. For this purpose, we will use proteomic approaches, qRT-PCR, transcriptional reporters and molecular microbiology.
- (ii) identify the transcriptional regulators and study the molecular mechanisms involved in this synchronize of the expression of the different iron uptake pathways;
- (iii) develop a mathematical model to decipher the regulatory network involved and help to identify the most promising iron uptake pathway(s) in P. aeruginosa genome for antibiotic vectorization.
This innovative and interdisciplinary project, is based on solid preliminary data involving 4 partners with complementary skills. The data we expect will provide fundamental understandings of how the human opportunist human pathogen P. aeruginosa adapts, selects, regulates, optimizes and synchronizes the expression of its iron uptake pathways to environmental changes and will also give new insight on the strategies developed by P. aeruginosa in the competition for iron with the host during infection. P. aeruginosa is a pathogen particularly dangerous for patients with chronic lung diseases and the World Health Organization has recently listed P. aeruginosa as one of three bacterial species in which there is a critical need for the development of new antibiotics to treat infections. With the data generated, we should as well be able to identify the best iron uptake pathways present in P. aeruginosa genome for efficient antibiotic uptake via siderophores.

Project coordination

Isabelle Schalk (Biotechnologie et signalisation cellulaire)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

BSC Biotechnologie et signalisation cellulaire
ICube Laboratoire des sciences de l'Ingénieur, de l'Informatique et de l'Imagerie
IPHC LSMBO
P3Cell Université Reims Champagne-Ardenne

Help of the ANR 693,142 euros
Beginning and duration of the scientific project: December 2022 - 48 Months

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