The production of metallo-β-lactamase (MBLs) accounts for antimicrobial resistance (AMR) to β-lactam antibiotics including penicillins and carbapenems.1 Inhibitors against different subclasses of MBLs are urgently needed. Previously, we discovered that Bi(III)- and Au(I)-based drugs serve as effective inhibitors to B1 (e.g., NDM-1+) and B2 (e.g., CphA+) subclass MBLs.2,3 In this study, we demonstrated Au(I)-based agents including auranofin (AUR) and Ga(III)-based agents including gallium citrate (GaCit), as broad-spectrum inhibitors of MBLs including B2 (e.g., CphA+ and Sfh-I+) and B3 (e.g., SMB-1+) subclass MBLs. Several Au(I)-based and Ga(III)-based agents demonstrated synergism when co-treated with meropenem (MER) against the tested MBL+ E.coli. The co-treatment of AUR with MER could reduce the minimum inhibitory concentration (MIC) of MER by 16-fold and 32-fold against CphA+ and SMB-1+ bacteria respectively. Six new Ga(III)-based agents reduced the MIC of MER by 8-fold to 16-fold against SMB-1+ bacteria, resulting in fractional inhibitory concentration indexes (FICI) of < 0.5. Remarkable reductions in bacterial load were also observed in CphA+ bacteria-infected mammalian cells and murine peritonitis infection model with MER-AUR co-treatment. We conclude that AUR and GaCit, along with related Au(I) and Ga(III) drugs, as broad-spectrum inhibitors of MBLs would largely broaden the therapeutic options in treating the infections caused by multidrug-resistant superbugs.

We thank the Research Grants Council (RGC) (R7070-18, 17308921, 2122-7S04) and Innovative Technology Commission of Hong Kong, the University of Hong Kong (URC and Norman & Celia Yip Foundation) for financial support.

1. Brown E.D.; Wright G.D. Nature, 2016, 529, 336-343.
2. Wang R.; Lai T.P.; Gao P.; Zhang H.; Ho P.L.; Woo P.C.Y.; Ma G.; Kao R.Y.T.; Li H.; Sun H. Nat. Commun., 2018, 9, 439.
3. Sun H.; Zhang Q.; Wang R.; Wang H.; Wong Y.T.; Wang M.; Hao Q; Yan A.; Kao R.; Ho P.L.; Li H. Nat. Commun., 2020, 11, 5263.