Seminar by a new researcher: Dr Kevin ANTRAYGUES

Dr Kevin ANTRAYGUES

Laboratoire de chimie de coordination

Fighting antimicrobial resistance: from modifications of natural products to antibiotic-siderophore hybrids

Antimicrobial resistance was associated with nearly 5 million deaths in 2021, and this number is expected to double by 2050.[1] To fight this global health threat, new antibiotics must be developped.

In this talk, I will first present the project I was involved during my thesis to overcome limitations of rifabutin, a semi-synthetic antibiotic with promising activities against two highly resistant bacteria: Acinetobacter baumannii and Mycobacterium abscessus. Concerning A. baumannii infections, water-soluble prodrugs of rifabutin were synthesized to allow an intraveinous administration.[2] A comprehensive studies of the physchem and pharmacokinetic properties of these prodrugs was conducted in vitro and in vivo. Regarding M. abscessus infections, modifications of rifabutin were performed to prevent inactivation by the bacteria.[3-6] Promising compounds with a very high potency against M. abscessus were identified through parallel synthesis and subsequent in vitro testing.

In the second part of the talk, I will discuss the project I am currently developping at the LCC in order to fight Gram-negative bacteria, a class of micro-organisms mainly involved in antimicrobial resistance. Assisted by molecular modelling, I designed hybrids of an antibiotic and a siderophore, a molecule able to chelate ferric ion. These chimeras could be recognized by siderophore receptors expressed at the surface of Gram-negative bacteria: the active transport inside the pathogen would thus lead to an improved activity of the hybrid compared to the antibiotic alone.

Références

[1] GBD 2021 Antimicrobial Resistance Collaborators.The Lancet 2024, 404 (10459), 1199–1226.

[2] Antraygues, K.; Maingot, M.; Schellhorn, B.; Trebosc, V.; Gitzinger, M.; Deprez, B.; Defert, O.; Dale, G.E.; Bourotte, M.; Lociuro, S.; Willand, N. Eur. J. Med. Chem. 2022, 238, 114515.

[3] Antraygues, K.; Bourotte, M.; Dale, G.E.; Defert, O.; Gitzinger, M.; Lociuro, S.; Maingot, M.; Trebosc, V.; Willand, N. WO2024068926A1, 2024.

[4] Antraygues, K.; Bourotte, M.; Dale, G.E.; Defert, O.; Dreneau A.; Gitzinger, M.; Lociuro, S.; Maingot, M.; Michelotti A.; Trebosc, V.; Willand, N.; Khan, N.; Hofmann, L.; Miljkovic, M. WO2024165591A1, 2024.

[5] Antraygues, K.; Bourotte, M.; Dale, G.E.; Defert, O.; Gitzinger, M.; Lociuro, S.; Maingot, Mathieu; Trebosc, V.; Willand, N. WO2023118319A1, 2023.

[6] Antraygues, K.; Bourotte, M.; Dale, G.E.; Defert, O.; Gitzinger, M.; Lociuro, S.; Maingot, Mathieu; Trebosc, V.; Willand, N. WO2023198597A1, 2023.