Abstract
The rise of antimicrobial resistance has necessitated novel strategies to efficiently combat pathogenic bacteria. Metal‐based compounds have been proven as a possible alternative to classical organic drugs. Here, we have assessed the antibacterial activity of seven gold complexes of different families. One compound, a cyclometalated Au(III) C^N complex, showed activity against Gram‐positive bacteria, including multi‐drug resistant clinical strains. The mechanism of action of this compound was studied in Bacillus subtilis. Overall, the studies point towards a complex mode of antibacterial action, which does not include induction of oxidative stress or cell membrane damage. A number of genes related to metal transport and homeostasis were upregulated upon short treatment of the cells with gold compound. Toxicity tests conducted on precision‐cut mouse tissue slices ex vivo revealed that the organogold compound is poorly toxic to mouse liver and kidney tissues, and may thus, be treated as an antibacterial drug candidate.
Highlights
The interest in using gold-based substances for therapeutic applications dates back to ancient times and was an important aspect of alchemy in Medieval Europe and in the Renaissance period, when gold was an essential ingredient of so-called aurum vitae medicines.[1]
Minimum Inhibitory Concentrations (MICs) for the seven Au(III) compounds were determined by broth microdilution against E. coli MG1655 (Gram-negative bacterium) and B. subtilis 168 (Grampositive bacterium)
While all the compounds were inactive towards E. coli, complexes 1 and 4 showed an inhibitory effect on the growth of B. subtilis colonies (Table 1, Table S1), with MIC values only slightly higher than Kanamycin,[29] a potent antibiotic used as positive control (12.5 μM and 6.25 μM, respectively for 1 and 4, vs 3.12 μM)
Summary
The interest in using gold-based substances for therapeutic applications dates back to ancient times and was an important aspect of alchemy in Medieval Europe and in the Renaissance period, when gold was an essential ingredient of so-called aurum vitae medicines.[1]. Arca and co-workers reported on the promising antimicrobial activity of cyclometalated Au(III) complexes against Staphylococcus strains, in-depth mechanistic studies were not conducted.[19] The clinical relevance of some bis(pyrrolide-imine) Au(III) macrocycles as topoisomerase 1A inhibitors was demonstrated by their antibacterial effects in a panel of diverse M. tuberculosis and M. abscessus clinical isolates.[20] so far only limited attention has been paid to the application of Au(III) compounds as potential antimicrobial agents and to the elucidation of their modes of action In this context, we decided to expand the investigation on Au(III) complexes and selected seven representative molecules – featuring bidentate N^N ligands, cyclometalated bidentate C^N and terdentate C^N^N scaffolds, respectively – for antibacterial screening (compounds 1–7, Figure 1). Reaction of cyclometalated Au(III) complexes 1–3 with cysteine residues
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