Antimicrobial Activities of Synthetic Bismuth Compounds against Clostridium difficile

In the majority of patients, predisposition to infection with Clostridium difficile is induced by the disruption of the normal intestinal flora by antibiotic therapy (5). While vancomycin and metronidazole treatment of antibiotic-associated diarrhea and pseudomembranous colitis caused by this bacterium is effective, relapses do occur in up to 20% of patients, and these patients require further antimicrobial therapy (19). In view of such difficulties, other approaches to treatment and cure have been sought, such as biotherapy (18). There clearly is a need to develop new treatments for this potentially life-threatening disease. Bismuth compounds have proven utility as fungicides and antitumor agents and have been used to treat a variety of medical disorders for more than 200 years (4, 13). Most obvious has been the widespread use of bismuth compounds, mainly colloidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS), in the treatment of duodenal ulcers (25, 26), gastritis, chronic diarrhea, traveler’s diarrhea (11, 22), and acute diarrhea in children (20). A preliminary report (12) suggested that children with C. difficile colitis responded to treatment with BSS, and this concept was supported by an experimental model of C. difficile colitis in hamsters (6). However, the mechanism of therapeutic activity of bismuth compounds is not known, and their further development will require a fundamental understanding of the chemistry involved. The complex chemical nature of the common commercial bismuth compounds CBS and BSS has restricted the characterization and impeded the systematic development of new compounds. In addition to the many reports relating to BSS and CBS, some investigators have endeavored to synthesize new bismuth-containing compounds which might have heightened antibacterial activities (1, 2, 3, 8, 9, 10, 24). Asato et al. (3) produced three compounds with activity against Helicobacter pylori. The activities of those compounds were comparable to that of CBS. The compounds also possessed urease inhibitory activity. Domenico et al. (10) have explored the enhancement of antibacterial activities of bismuth-salts in the presence of lipophilic thiol chelators, mixtures which likely contain compounds earlier described by our laboratory (1, 2). In this context we initiated the present study to address structure-function relationships of bismuth-chelate complexes (thiabismuth heterocyles) against selected bacterial species as a way of elucidating the mechanism of action of bismuth against selected bacteria. To facilitate these studies we synthesized and tested a systematic series of structurally simple thiabismuth heterocycles (1, 2) to assess the potential structure-activity relationship of bismuth. The thermodynamically favored chelated environment and the prominent thiophilicity of bismuth make these compounds ideal initial candidates for such a study in that they are likely to retain their structures in solution for the duration required for biological testing. In this report we demonstrate the antimicrobial activities of these compounds against C. difficile and, in comparison, their activities against four species of gram-negative bacteria. Also compared are the activities of these compounds with those of three CBS compounds and ranitidine bismuth citrate. (Part of this work was presented at the 64th Conjoint Meeting on Infectious Diseases of the Canadian Association for Clinical Microbiology and Infectious Diseases, Hamilton, Ontario, Canada, 10 to 14 November 1996 [12a], and at the Second International Meeting on the Molecular Genetics and Pathogenesis of the Clostridia, Onzain, France, 22 to 25 June 1997 [12b].)