Abstract

Antibiotics are considered as highly effective treatments of pathogenic infections, until the occurrence of wide and rapid spread of resistance bacteria, and the scarcity of new antibiotics(1). Burkholderia cepacia complex (Bcc), often causing pneumonia and cystic fibrosis (CF), cannot be eradicated by current therapies involving double or triple antibiotics combinations, owing to its highly intrinsic resistance to conventional antibiotics(2). Previously, we have demonstrated that a metallodrug or metal complex can restore the activity of certain antibiotics (3-7). Herein, we show that bismuth drugs could inhibit the growth of clinical antibiotic-resistant Bcc strains, with MIC (20 μg/mL) comparable to that for Helicobacter pylori. The mode of antimicrobial action of bismuth(III) against Bcc was investigated by using a home-made GE-ICP-MS, enabling proteome-wide tracking of more than 20 bismuth-binding targets. Bioinformatics analysis reveals that Bi(III) eradicates B. cepacia mainly through impairing aerobic respiration chain, TCA cycle, energy production. Moreover, bismuth could not only kill Bcc synergistically with antibiotics and slow down high level resistance development, but also exhibited excellent activity against notorious biofilm and persister cells. Our findings offer a new strategy for combating drug resistant Bcc infections via combination of bismuth drugs with antibiotics.  

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

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