Structure-activity studies reveal efficient inactivation of urease by Ebsulfur-based compounds

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Microbiology

Background:

• Antimicrobial resistance is a major global health challenge requiring novel therapeutic strategies.
• Urease-expressing bacteria are significant pathogens, making urease an attractive drug target.
• Organoselenium compounds like Ebselen show urease inhibition but have toxicity issues.

Purpose of the Study:

• To evaluate Ebsulfur derivatives as potential urease inhibitors and antimicrobial agents.
• To explore a safer alternative to Ebselen for targeting urease-expressing pathogens.

Main Methods:

• Biochemical assays were used to test the urease inhibitory activity of three Ebsulfur derivatives.
• X-ray crystallography was employed to determine the structures of enzyme-inhibitor complexes.

Main Results:

• The Ebsulfur derivatives effectively inhibited both bacterial (Sporosarcina pasteurii) and plant (Canavalia ensiformis) urease.
• Inhibition occurred in the low micromolar range.
• X-ray structures revealed a mechanism involving di-sulfuration of the essential αCys322 residue.

Conclusions:

• Ebsulfur derivatives demonstrate significant urease inhibitory potential.
• These compounds represent a promising avenue for developing new antimicrobial strategies against resistant bacteria.
• The findings contribute to addressing the stagnation in antibiotic development.