Navigation into novel medical use of bismuth based agents as breakers of antibiotic resistance and antagonist against chemotherapy side effects

Abstract

Bismuth-based agents have been applied in the treatment of diverse diseases for over two-hundred years owing to their economic, non-toxic, stable and easy-to-use characteristics. Nowadays, the most clinically relevant bismuth medicines such as bismuth subsalicylate, colloidal bismuth subcitrate (CBS), ranitidine bismuth citrate find their main medical use in the treatment of Helicobacter pylori (H. pylori)-associated gastrointestinal diseases. But the rich biological chemistry of bismuth endows it with more potentials in medication other than eradication of H.pylori. In this thesis, the roles of bismuth-based agents in the combat with antibiotic resistance and chemotherapeutic drug induced side effects are explored. A battery of bismuth complexes with bismuth coordinating to nitrogen, oxygen and/or sulfur containing ligands are prepared to establish a compound bank in search of the drug candidates with desired properties. A primary screening gives thirteen bismuth compounds that exhibited antibacterial activity against three Burkholderia cepacia complex (BCC) with MIC ranging from 0.5 to 128 µg mL-1. CBS is found to significantly resensitize BCC to antibiotics, lower the mutation prevention concentration by 2~32-fold and slow down resistance development by 4 folds when it is used together with tetracycline. Either physical mixing or complexation of bismuth with a small molecule Hinokitiol dramatically enhanced the antimicrobial activity of bismuth compounds against both planktonic and biofilm Pseudomonas aeruginosa, which shed light on a novel strategy to tune the antimicrobial activity of Bi(III) compounds. Metallo-β-lactamase (MBL) such as NDM-1 is a zinc enzyme that empowers bacteria with resistance to almost all β-lactam antibiotics. Bismuth compounds are found to be a novel class of MBL inhibitor. Through metal displacement mechanism, bismuth compounds resensitize a panel of MBL positive bacteria to meropenem with its MIC dropped by 8~32 folds. The bioactivity of compounds was found to correlate with the ligand type and coordination environment of Bi(III) ions. CBS suppresses the resistance development of NDM-1 positive E. coli. Animal study shows that the combination therapy of CBS and meropenem greatly raises the survival rate of infected mice in systemic infection model and reduce significantly bacterial loads in mouse bladder in urinary tract infection model. Several bismuth drugs such as BSS and CBS are reported to antagonize cisplatin-induced nephrotoxicity via the induction of metallothionein. Through cell-based screening, two types of bismuth compounds, bismuth tetraphenylporphyrinate (Bi(TPP)) and bismuth thiolates are identified to have higher cytoprotective activity than either CBS or BSS. Animal studies reveal that pretreatment of Bi(TPP) significantly protect the renal function and raise the survival rate of mice receiving cisplatin administration while showing no compromisation on the antineoplastic action of CDDP. Protective mode of action of Bi(TPP) was unveiled via transcriptomic analysis. Bi(TPP) was found to upregulate some key survival factors i.e., Pik3cd, Egf, Igf2 and downregulate some key death factors i.e., Fas, Tnf, Casp8 in signaling pathway related to apotosis and inflammation. Bioinformatics study further indicates that, beyond MT induction, protection offered by Bi(TPP) tightly correlates with protein binding, ion binding, catalytic activity, apoptotic signaling.