Design and synthesis of novel bismuth-based materials as promising antimicrobials for tackling periodontopathogens and potential agents for modulating oral ecological conditions

Abstract

Bismuth drugs, commonly used for treating Helicobacter pylori-associated gastrointestinal infections, have been considerably repositioned to tackle the key oral/periodontal pathogen Porphyromonas gingivalis (Pg). Combining these metallodrugs with antibiotics can synergistically eliminate the recalcitrant Pg persisters. However, current bismuth drug formulations have limited water solubility and bioavailability; hence, precise delivery of co-administrated drugs is highly challenging. Essentially, bismuth ions with high affinities towards oxygen, nitrogen and sulfur can be facilely constructed into metal-organic frameworks (MOFs) and other materials by optimizing various synthetic parameters and routes. These resultant particles with antimicrobial effects acquired from the metals act as an adjunct to improve the efficacy of the original drugs. Moreover, they enable the progressively controlled release of drugs and generate synergistic effects after co-administration with antibiotics. Indeed, these materials have emerged as promising therapeutic approaches to tackling current biomedical challenges, such as overcoming the antibiotic resistance crisis for better oral and general healthcare. In this work, various bismuth-based particles were synthesized, and their morphological and size profiles were analyzed with electron microscopy images (Chapter III). Amongst, highly uniformed particles with ellipsoid- and rod-like shapes (denoted as Ellipsoids and Rods, respectively) were selected and thoroughly examined. Specifically, pore-containing Rods, stacked up by almond-flake-like intermediates within a ‘two-step’ crystallization process, were confirmed as MOFs with an aligned crystallinity of CAU-17. Notably, microscale Rods could be precisely controlled to nanoforms by changing the amounts of metal ions and ligands presented in the solution (Chapter IV). Regarding the biological activities, both particles were highly compatible with human gingival fibroblasts and human gingival epithelial cells (HGECs), and possessed outstanding antibacterial effects on the Gram-negative periodontal anaerobes like Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum and Pg. Particularly, these particles could efficiently damage the bacterial membranes and eliminate the 3-day-old biofilms of Pg (Chapter V). Next, the antimicrobial effects of nanoscale Rods (Bi-MOFsNano) and emodin (an active component of several plants used in Chinese medicine) were evaluated against selected periodontopathogens. Further experiments were undertaken to investigate whether the co-administration of Bi-MOFsNano and emodin could eliminate the noxious intracellular Pg in the host cells. For determining the synergistic activity of Bi-MOFsNano and emodin, a checkerboard assay was carried out to measure the fractional inhibitory concentration (FIC) index. The co-administration could synergistically suppress the growth of planktonic Pg cells (FIC ≤ 0.5), while both agents at low concentrations exhibited no detectable cytotoxicity of HGECs, as demonstrated in the cell viability assay. Remarkably, the synergistic pairs of Bi-MOFsNano and emodin could inhibit the intracellular Pg in HGECs (Chapter VI). The present study presents two novel approaches to constructing bismuth-based particles both efficiently and facilely. Importantly, Bi-MOFs as a bismuth reservoir show effective antibacterial effects on the keystone periodontopathogen Pg. In synergistic combination with emodin, these particles can serve as an innovative platform to precisely deliver drugs via topical administrations, while simultaneously tackling various pathogens and modulating the resultant immunoinflammatory responses. This work may shed light on enriching antibiotic-free methods by administrating metallic drugs and enhancing oral and general healthcare in the near future.