Bismuth drug eradicates multi-drug resistant <i>Burkholderia cepacia</i> complex <i>via</i> aerobic respiration

<i>Burkholderia cepacia</i> complex (Bcc) is a group of Gram-negative opportunistic pathogens highly responsible for chronic pulmonary infection in cystic fibrosis (CF). Current therapies involving double or triple antibiotic combinations can rarely eradicate the pathogen in chronically infected patients owing to its intrinsic resistance to a variety of antibiotics. Herein, we show that a bismuth drug (and related compounds) could inhibit the growth of clinically antibiotic-resistant Bcc strains, with MIC (<i>ca.</i> 25 μg mL^-1) comparable to that for <i>Helicobacter pylori</i>, and the combination of a bismuth drug and antibiotics also demonstrated excellent activity against biofilm and persisters of Bcc. Importantly, the <i>in vitro</i> antimicrobial activity of a bismuth drug could be well translated into <i>in vivo</i> evidenced by about 50% survival rates in the <i>Galleria mellonella</i> infection model. Transcriptomics analysis shows the dynamic responses of Bcc to bismuth treatment. Using a homemade metalloproteomic approach, we could identify 26 Bi^III-binding proteins (15 cytosolic proteins and 11 membrane proteins). Further mechanistic studies reveal that bismuth drugs initially target the TCA cycle through the binding and inactivation of a series of enzymes including malate dehydrogenase (MDH), malate synthase (AceB), and succinyl coenzyme A synthetase (SCS), then interfere oxidative phosphorylation through binding to terminal oxidases, <i>i.e.</i>, CyoC and CydA, to disrupt electron transport chain, eventually, disrupt protein translation and ribosome <i>via</i> binding and down-regulation of key proteins. Our studies highlight the great potential of bismuth drugs and/or compounds to treat multidrug-resistant Bcc infections.