According to WHO, it is estimated that people died from superbugs infections will be higher than cancers in 2050 1 as more antibiotics failed even the last drug of resort like carbapenem and vancomycin.2 Due to the multiple target feature, metal compounds have much less chances to develop resistance. We recently found that bismuth citrate and relevant complexes, serving as NDM-1 inhibitors, restored meropenem activity both in vitro and in vivo (mice) as well as slowed down the resistance development by 4-fold.3 

Herein, 50 Bi(III) complexes were designed, synthesized and characterized by NMR and ESI-MS, we found that Bi(III) thiolate and some thiocarbamate complexes showed good synergy (FIC index below 0.3) with macrolides, tetracyclines, quinolones and some β-lactam antibiotics against P. aeruginosa PAO1 and, importantly, are non-toxic even at above 256 µM in A549 cells. Moreover, conjugates of Bi(III) complexes with modified antibiotics exhibited enhanced activity against PAO1 and Methicillin-resistant Staphylococcus aureus (MRSA). Our work may open a new horizon for fighting against infections by superbugs.

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

References

(1) Laxminarayan R et al. (2022). Lancet, 399(10325), 629-655.

(2) Davido B, Moussiegt A, Dinh A (2018). Antimicrob Resist Infect Control, 7, 100.

(3) Wang R, Lai TP, Gao, P & Sun HZ. et al. (2018). Nat Commun 9, 439.