Anti-Staphylococcal Activity of the Auranofin Analogue Bearing Acetylcysteine in Place of the Thiosugar: An Experimental and Theoretical Investigation

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 8; p. 2578
• Main Authors: Chiaverini, Lorenzo, Pratesi, Alessandro, Cirri, Damiano, Nardinocchi, Arianna, Tolbatov, Iogann, Marrone, Alessandro, Di Luca, Mariagrazia, Marzo, Tiziano, La Mendola, Diego
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16.04.2022; MDPI
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; Acetylcysteine - therapeutic use; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibacterial activity; antibacterial agents; antibiotic resistance; Antibiotics; Antimicrobial agents; Arthritis; auranofin; Auranofin - chemistry; Auranofin - pharmacology; Bacterial diseases; Bacterial infections; Binding; Biological activity; Drug resistance; Gold; Gram-positive bacteria; Human serum albumin; Humans; Ligands; Mode of action; Nosocomial infections; Oral administration; Peptides; Pharmacology; Proteins; Rheumatoid arthritis; S. aureus; S. epidermidis; Serum albumin; Staphylococcal Infections - drug therapy; Staphylococcus aureus; Staphylococcus infections; S. epidermidis; gold; acetylcysteine; auranofin; S. aureus; antibiotic resistance; antibacterial agents; ESI-MS; computational chemistry; metal-based drugs
• DOI: 10.3390/molecules27082578
• ISSN: 1420-3049

Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt ] . Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against , whereas it is about 20 times less effective against . Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt ] fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH , corresponding to the tryptic C-terminal fragment (488-499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au-S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply.