title: Development of ebsulfur analogues as potent antibacterials against methicillin-resistant Staphylococcus aureus.
abstract: Antibiotic resistance is a worldwide problem that needs to be addressed. Staphylococcus aureus is one of the dangerous "ESKAPE" pathogens that rapidly evolve and evade many current FDA-approved antibiotics. Thus, there is an urgent need for new anti-MRSA compounds. Ebselen (also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one) has shown promising activity in clinical trials for cerebral ischemia, bipolar disorder, and noise-induced hearing loss. Recently, there has been a renewed interest in exploring the antibacterial properties of ebselen. In this study, we synthesized an ebselen-inspired library of 33 compounds where the selenium atom has been replaced by sulfur (ebsulfur derivatives) and evaluated them against a panel of drug-sensitive and drug-resistant S. aureus and non-S. aureus strains. Within our library, we identified three outstanding analogues with potent activity against all S. aureus strains tested (MIC values mostly ⩽2μg/mL), and numerous additional ones with overall very good to good antibacterial activity (1-7.8μg/mL). We also characterized the time-kill analysis, anti-biofilm ability, hemolytic activity, mammalian cytotoxicity, membrane-disruption ability, and reactive oxygen species (ROS) production of some of these analogues.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
authors.forename: Huy X
authors.initials: HX
authors.lastname: Ngo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
authors.forename: Sanjib K
authors.initials: SK
authors.lastname: Shrestha
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536-0596, USA. Electronic address: sylviegtsodikova@uky.edu.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054833:Isoindoles; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen
keywords: Antibiotic; Benzisothiazolinone; Biofilm; ESKAPE; Reactive oxygen species (ROS); Resistance