Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights.

Autor:	Ratia C; Barcelona Institute for Global Health (ISGlobal), Universitat de Barcelona, Barcelona, Spain., Ballén V; Barcelona Institute for Global Health (ISGlobal), Universitat de Barcelona, Barcelona, Spain., Gabasa Y; Barcelona Institute for Global Health (ISGlobal), Universitat de Barcelona, Barcelona, Spain., Soengas RG; Área de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, Spain., Velasco-de Andrés M; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain., Iglesias MJ; Área de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, Spain., Cheng Q; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Lozano F; August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.; Servei d'Immunologia, Centre de Diagnòstic Biomèdic, Hospital Clínic de Barcelona, Barcelona, Spain.; Department de Biomedicina, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain., Arnér ESJ; Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.; Department of Selenoprotein Research and the National Tumor Biology Laboratory, Budapest, Hungary., López-Ortiz F; Área de Química Orgánica, Centro de Investigación CIAIMBITAL, Universidad de Almería, Almería, Spain., Soto SM; Barcelona Institute for Global Health (ISGlobal), Universitat de Barcelona, Barcelona, Spain.; CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in microbiology [Front Microbiol] 2023 Jun 02; Vol. 14, pp. 1198473. Date of Electronic Publication: 2023 Jun 02 (Print Publication: 2023).
DOI:	10.3389/fmicb.2023.1198473
Abstrakt:	Introduction: Antimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate. Methods and Results: The Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity. Discussion: Overall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo , and non-conventional mechanism of action. Competing Interests: SS, CR, RS, MI, and FL-O have patents on complex 1 and 2. QC and EA are shareholders of Selenozyme AB selling recombinant selenoproteins, including human TrxR. EA is a shareholder of Thioredoxin Systems AB, developing antibiotics targeting the bacterial thioredoxin system. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Ratia, Ballén, Gabasa, Soengas, Velasco-de Andrés, Iglesias, Cheng, Lozano, Arnér, López-Ortiz and Soto.)
Databáze:	MEDLINE
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