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6z4n

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CRYSTAL STRUCTURE OF OASS COMPLEXED WITH UPAR INHIBITOR

Structural highlights

6z4n is a 2 chain structure with sequence from Salmonella enterica subsp. enterica serovar Typhimurium str. LT2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.2Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CYSK_SALTY Two cysteine synthase enzymes are found. Both catalyze the same reaction. Cysteine synthase B can also use thiosulfate in place of sulfide to give cysteine thiosulfonate as a product.

Publication Abstract from PubMed

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 O-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, Escherichia coli, Salmonella enterica serovar Typhimurium, Klebisiella pneumoniae, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Staphylococcus pseudintermedius. 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 A 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.

Investigational Studies on a Hit Compound Cyclopropane-Carboxylic Acid Derivative Targeting O-Acetylserine Sulfhydrylase as a Colistin Adjuvant.,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 CS, Campanini B, Costantino G ACS Infect Dis. 2021 Feb 12;7(2):281-292. doi: 10.1021/acsinfecdis.0c00378. Epub , 2021 Jan 29. PMID:33513010^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ 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 CS, 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. 2021 Feb 12;7(2):281-292. PMID:33513010 doi:10.1021/acsinfecdis.0c00378