As pathogenic microorganisms have a strong capacity to develop resistance, particularly against new compounds belonging to existing antibiotic families, new anti-infectives with unprecedented mechanisms of action are urgently needed.
The biosynthesis of terpenoids represents an attractive source of drug. Terpenoids are essential metabolites produced by the assembly of two precursors. These precursors are produced by two different metabolic pathways : the mevalonate (MVA) pathway and the methylerythritol phosphate (MEP) pathway. Humans use the MVA pathway exclusively, making the MEP pathway, found in bacteria and sporozoan parasites, a prime therapeutic target against pathogens.
In this study, carried out by the synchrotron group of the IBS, in collaboration with Hannah Hirsch’s team (HZI, Saarbrüken), the researchers present the resolution of the first crystal structure of the third enzyme of the Pseudomonas aeruginosa MEP pathway (Pa-IspD). They also present the discovery and optimization of a new class of compounds binding to the active site of Pa-IspD, identified by crystallographic screening of a library of fragments.
As the newly synthesized compounds have improved affinity for Pa-IspD, they represent a first step in the search for anti-infective molecules with a new mechanism of action.
Fragment Discovery by X-Ray Crystallographic Screening Targeting the CTP Binding Site of Pseudomonas aeruginosa IspD. Willocx D, D’Auria L, Walsh D, Scherer H, Alhayek A, Hamed MM, Borel F, Diamanti E, Hirsch AKH. Angewandte Chemie International Edition 2025 ; 64(6):e202414615.
Contact : Franck Borel (IBS/Synchrotron group)