Structural insights into the interactions between an enzyme and a hit compound for the discovery of drugs

An innovative approach to treat bacterial infections is based on the design of new drugs capable of enhancing antibiotic activity by reducing the therapeutic dose of conventional antibiotics and minimizing resistance. It is necessary to identify compounds able to selectively target a key enzyme, such as the enzyme involved in the microbial reductive sulfur assimilation pathway.

Elettra's contribution
Synchrotron X-ray diffraction analysis allowed to obtain the 3D structure of a hit compound in complex with the target enzyme, confirming that it binds in the active site and competes with the substrate. Thus, structural information about the interaction between the enzyme and this class of competitive inhibitors has been showed for the first time.
This result is very relevant for the design of better ligands of enzymes and will pave the way for further cycles of medicinal chemistry optimization in the context of the multiparametric optimization process to develop a new class of antimicrobial drugs.

Facility: XRD1 Beamline.

Bibliography: G. Annunziato et al., “Investigational Studies on a Hit Compound Cyclopropane–Carboxylic Acid Derivative Targeting O-Acetylserine Sulfhydrylase as a Colistin Adjuvant”, ACS Infect. Dis. 2021, 7, 281–292. DOI: 10.1021/acsinfecdis.0c00378