6Z4N

CRYSTAL STRUCTURE OF OASS COMPLEXED WITH UPAR INHIBITOR

This is a non-PDB format compatible entry.

Summary for 6Z4N

• Entry DOI: 10.2210/pdb6z4n/pdb
• Descriptor: Cysteine synthase A, PYRIDOXAL-5'-PHOSPHATE, (1~{S},2~{S})-1-[(4-methylphenyl)methyl]-2-phenyl-cyclopropane-1-carboxylic acid, ... (7 entities in total)
• Functional Keywords: cystein biosynthesis, beta replacement enzyme, plp dependent enzyme, homodimer, lyase, inhibitor
• Biological source: Salmonella enterica subsp. enterica serovar Typhimurium str. LT2
• Total number of polymer chains: 2
• Total formula weight: 71008.08

Authors

Demitri, N.,Storici, P.,Campanini, B. (deposition date: 2020-05-25, release date: 2021-04-07, Last modification date: 2024-01-24)

Primary citation

Annunziato, G.,Spadini, C.,Franko, N.,Storici, P.,Demitri, N.,Pieroni, M.,Flisi, S.,Rosati, L.,Iannarelli, M.,Marchetti, M.,Magalhaes, J.,Bettati, S.,Mozzarelli, A.,Cabassi, C.S.,Campanini, B.,Costantino, G.
Investigational Studies on a Hit Compound Cyclopropane-Carboxylic Acid Derivative Targeting O -Acetylserine Sulfhydrylase as a Colistin Adjuvant.
Acs Infect Dis., 7:281-292, 2021

PubMed Abstract: Antibacterial adjuvants are of great significance, since they allow the therapeutic dose of conventional antibiotics to be lowered and reduce the insurgence of antibiotic resistance. Herein, we report that an acetylserine sulfhydrylase (OASS) inhibitor can be used as a colistin adjuvant to treat infections caused by Gram-positive and Gram-negative pathogens. A compound that binds OASS with a nM dissociation constant was tested as an adjuvant of colistin against six critical pathogens responsible for infections spreading worldwide, , serovar Typhimurium, , , methicillin-resistant , and . The compound showed promising synergistic or additive activities against all of them. Knockout experiments confirmed the intracellular target engagement supporting the proposed mechanism of action. Moreover, compound toxicity was evaluated by means of its hemolytic activity against sheep defibrinated blood cells, showing a good safety profile. The 3D structure of the compound in complex with OASS was determined at 1.2 Å resolution by macromolecular crystallography, providing for the first time structural insights about the nature of the interaction between the enzyme and this class of competitive inhibitors. Our results provide a robust proof of principle supporting OASS as a potential nonessential antibacterial target to develop a new class of adjuvants and the structural basis for further structure-activity relationship studies.

PubMed: 33513010
DOI: 10.1021/acsinfecdis.0c00378

Experimental method

X-RAY DIFFRACTION (1.2 Å)