jm9b00550_si_001.pdf (10.13 MB)
Synthesis and Structure–Activity Relationship Study of Antimicrobial Auranofin against ESKAPE Pathogens
Version 2 2019-10-18, 13:33
Version 1 2019-08-21, 13:37
journal contribution
posted on 2019-10-18, 13:33 authored by Bin Wu, Xiaojian Yang, Mingdi YanAuranofin, an FDA-approved arthritis
drug, has recently been repurposed
as a potential antimicrobial agent; it performed well against many
Gram-positive bacteria, including multidrug resistant strains. It
is, however, inactive toward Gram-negative bacteria, for which we
are in dire need of new therapies. In this work, 40 auranofin analogues
were synthesized by varying the structures of the thiol and phosphine
ligands, and their activities were tested against ESKAPE pathogens.
The study identified compounds that exhibited bacterial inhibition
(MIC) and killing (MBC) activities up
to 65 folds higher than that of auranofin, making them effective against
Gram-negative pathogens. Both thiol and the phosphine structures influence
the activities of the analogues. The trimethylphosphine and triethylphosphine
ligands gave the highest activities against Gram-negative and Gram-positive
bacteria, respectively. Our SAR study revealed that the thiol ligand
is also very important, the structure of which can modulate the activities
of the AuI complexes for both Gram-negative and Gram-positive
bacteria. Moreover, these analogues had mammalian cell toxicities
either similar to or lower than that of auranofin.