ENHANCEMENT OF BISMUTH ANTIBACTERIAL ACTIVITY WITH LIPOPHILIC THIOL CHELATORS

The antibacterial properties of bismuth are greatly enhanced when bism uth is combined with certain lipophilic thiol compounds, Antibacterial activity was enhanced from 25- to 300-fold by the following seven dif ferent thiols, in order of decreasing synergy: 1,3-propanedithiol, dim ercaprol (BAL), dithiothreitol, 3-mercapto-2-butanol, beta-mercaptoeth anol, 1-monothioglycerol, and mercaptoethylamine, The dithiols produce d the greatest synergy with bismuth at optimum bismuth-thiol molar rat ios of from 3:1 to 1:1. The monothiols were generally not as synergist ic and required molar ratios of from I:1 to 1:4 for optimum antibacter ial activity, The most-active mono- or dithiols were also the most sol uble in butanol, The intensity of the yellow formed by bismuth-thiol c omplexes reflected the degree of chelation and correlated with antibac terial potency at high molar ratios, The bismuth-BAL compound (BisBAL) was active against most bacteria, as assessed by broth dilution, agar diffusion, and agar dilution analyses, Staphylococci (MIG, 5 to 7 mu M Bi3+) and Helicobacter pylori (MIG, 2.2 mu M) were among the most se nsitive bacteria, Gram-negative bacteria were sensitive (MIG, <17 mu M ). Enterococci were relatively resistant (MIG, 63 mu M Bi3+), The MIC range for anaerobes was 15 to 100 mu M Bi3+, except for Clostridium di fficile (MIC, 7.5 mu M). Bactericidal activity averaged 29% above the MIC. Bactericidal activity increased with increasing pH and/or increas ing temperature, Bismuth-thiol solubility, stability, and antibacteria l activity depended on pH and the bismuth-thiol molar ratio, BisBAL wa s stable but ineffective against Escherichia coli at pH 4, Activity an d instability (reactivity) increased with increasing alkalinity, BisBA L was acid soluble at a molar ratio of greater than 3:2 and alkaline s oluble at a molar ratio of less than 2:3, In conclusion, certain lipop hilic thiol compounds enhanced bismuth antibacterial activity against a broad spectrum of bacteria, The activity, solubility, and stability of BisBAL were strongly dependent on the pH, temperature, and molar ra tio. Chelation of bismuth with certain thiol agents enhanced the solub ility and lipophilicity of this cationic heavy metal, thereby signific antly enhancing its potency and versatility as an antibacterial agent.