Auranofin, a gold(I)-complex with tetraacetylated thioglucose and
triethylphosphine ligands, is an FDA-approved drug used as an
anti-inflammatory aid in the treatment of rheumatoid arthritis. In
repurposing auranofin for other diseases, it was found that the drug
showed significant activity against Gram-positive bacteria but was
inactive against Gram-negative bacteria. Herein, we report the design
and synthesis of gold nanoclusters (AuNCs) based on the structural motif
of auranofin. Phosphine-capped AuNCs were synthesized and glycosylated,
yielding auranofin AuNC analogues with mixed phosphine/thioglucose
ligand shells. These AuNCs were active against both Gram-negative and
Gram-positive bacteria, including a panel of resistant ESKAPE pathogens.
Notably, an auranofin analogue, a mixed-ligand 1.6 nm AuNC (<strong>4b</strong>) was ~4 times more active than auranofin against <em>Pseudomonas aeruginosa</em>,
while exhibiting 24 times lower toxicity against human A549 cells. The
enhanced antibacterial activity of these AuNCs was characterized by a
greater uptake of Au by the bacteria compared to Au<sup>I</sup>-complexes (20% for AuNC <strong>4b</strong>).
Additional factors include increased oxidative stress, moderate
inhibition of thioredoxin reductase (TrxR), and DNA damage. Most
intriguingly, the AuNCs were not affected by the bacterial outer
membrane (OM) barrier or by extracellular proteins. This contrasts with
Au<sup>I</sup>-complexes like auranofin that are susceptible to protein binding and hindered by the OM barrier.