6-months M2 Internship: Optimisation of The

**6-months M2 Internship: Optimisation of the efficacy of cefiderocol against Gram-negative bacteria by combining it with gallium**:

- Réf **ABG-125815**
- Stage master 2 / Ingénieur- Durée 6 mois- Salaire net mensuel 350- 16/09/2024- Inserm- Lieu de travail- Poitiers Nouvelle Aquitaine France- Champs scientifiques- Biologie
- Santé, médecine humaine, vétérinaire
- Mots clés- Microbiology, MIC determination, Time-kill curves, Whole Genome Sequencing, RT-qPCR-
- 10/10/2024**Établissement recruteur**:
**Site web**:
The research unit affiliated to the University of Poitiers and INSERM has been created in 2012 and comprises 20 permanent staff members (clinicians, pharmacists and scientists) and 13 students (PhD and master students).

The INSERM U1070 unit aim to optimize the antibiotic usage with a triple target:
To increase their efficacy,

To control the toxicity and

To limit the emergence of antibiotic resistance.

In order to do so, we are developping innovative PK/PD modelling approaches to select the best dosing regimen of antibiotics administered alone or in combination as well as the best route of administration and best formulation.

Inserm U1070 conducts translational research, from cells culture models to patients, by integrating microbiology, analytical chemistry, drug formulation, and in vivo preclinical experiments.

To date, Inserm U1070 received several grants from Region Nouvelle-Aquitaine, ANR, PHRC, JPIAMR, IMI and CPER-FEDER and has established collaborations with ANSES and several Universities in France (Paris Sud, Paris Diderot) and abroad (Dublin, Erasmus MC, Upssala, Hambourg, Catholic University of Louvain ), as well as leading pharmaceutical companies.

**Description**:
Antimicrobial resistance is a growing global crisis, particularly in gram-negative bacteria such as Klebsiella pneumoniae and Acinetobacter baumannii. The WHO has classified carbapenem-resistant strains of these bacteria as priority group 1, considering them critical threats to public health. Among the limited treatment options available, cefiderocol - a recently marketed antibiotic - stands out. This new antibiotic is composed of a cephalosporin chemically linked to a siderophore, a unique feature that reinforces its effectiveness against these resistant pathogens. The siderophore group binds iron, enabling the antibiotic to be actively transported into bacterial cells via iron uptake systems, thereby increasing its intracellular concentration. Despite its innovative mechanism, cases of resistance to cefiderocol have already been reported, highlighting the urgent need to optimise its efficacy in order to prevent the emergence of new resistances.

Recent research has revealed that gallium, a semi-metallic element, has antimicrobial activity against P. aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Gallium’s antimicrobial action derives from its ability to mimic ferric iron (Fe(III)) and inhibit iron-dependent enzymes. Gallium therefore has multiple targets, which reduces the likelihood of resistance developing. Ongoing clinical trials have shown promising results.
Given gallium’s ability to mimic iron, it seems possible to combine it with cefiderocol to improve their penetration of bacterial cells and boost their efficacy.
The aim of the project is to study the combination of cefiderocol with different gallium salts in order to increase its effectiveness against Gram-negative bacteria in WHO priority group 1.

Experimental plan
1. Screening of the cefiderocol-gallium combination against A. baumannii and K. pneumoniae:
To evaluate the efficacy of cefiderocol in combination with different gallium salts, we will perform MIC measurements and checkerboard experiments. Analysis of the antibacterial efficacy of the combinations will be quantified not only by calculating the fractional inhibitory concentration index (FICI), but also by assessing potency and maximum effect using an inhibitory Emax model.
2. Promising combinations will be further evaluated using bactericidal kinetics to observe the dynamics of antibacterial effect, and sequential MIC measurements to assess the frequency of resistance emergence, with or without gallium. Strains that develop resistance to cefiderocol will be fully sequenced to identify potential mutations, particularly in genes linked to iron or siderophore transporters.

This project is funded by a grant from Shionogi, the pharmaceutical company that developed cefiderocol.

**Profil**:
M1 student from microbiology field

**Prise de fonction**:

- 06/01/2025