Resistance to bismuth among gram-negative bacteria is dependent upon iron and its uptake.

Bismuth antimicrobial action is poorly understood. Many trivalent metals possess antibacterial activity, especially under low iron conditions. Protection of bacteria from the deleterious effects of bismuth and other trivalent metals was demonstrated in iron-fortified media. Near-equimolar quantities of Fe3+ neutralized the growth-inhibitory effects of 250 microM Bi3+. Resistance to bismuth action also depended on the production of virulence-related siderophores. Escherichia coli, Aeromonas hydrophila or Pseudomonas aeruginosa producing aerobactin, amonabactin or pyoverdin respectively, were most resistant to Bi3+. Enterochelin or pyochelin producers were less resistant to Bi3+, but more resistant than strains lacking siderophores. Purified pyoverdin restored Bi3+ resistance in a mutant lacking this siderophore, but not in one lacking the pyoverdin receptor. Bismuth-treated bacteria exhibited unique outer membrane proteins, similar in size to iron-repressible proteins. Thus, resistance to the inhibitory action of Bi3+ among Gram-negative bacteria is inversely related to iron concentration and strongly dependent on iron transport mechanisms. The data suggest that bismuth action is largely a nonspecific, competitive interference with iron-transport, related primarily to atomic valence Furthermore, resistance to Bi3+ among bacteria is predictive of virulence.

[1]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[2]  E. Weinberg.  Iron and infection , 1978, Microbiological reviews.

[3]  C. E. Lankford,et al.  Enterochelin (enterobactin): virulence factor for Salmonella typhimurium , 1979, Infection and immunity.

[4]  P. Williams,et al.  ColV plasmid-mediated, colicin V-independent iron uptake system of invasive strains of Escherichia coli. , 1980, Infection and immunity.

[5]  J. Neilands,et al.  Iron absorption and transport in microorganisms. , 1981, Annual review of nutrition.

[6]  J. Neilands.  Microbial iron compounds. , 1981, Annual review of biochemistry.

[7]  K. Konopka,et al.  Aerobactin-mediated utilization of transferrin iron. , 1982, Biochemistry.

[8]  C. D. Cox,et al.  Siderophore activity of pyoverdin for Pseudomonas aeruginosa , 1985, Infection and immunity.

[9]  T. Emery.  Exchange of iron by gallium in siderophores. , 1986, Biochemistry.

[10]  F. Wolff,et al.  Pharmacokinetics and Toxicity of Bismuth Compounds , 1989, Medical toxicology and adverse drug experience.

[11]  T. Sox,et al.  Binding and killing of bacteria by bismuth subsalicylate , 1989, Antimicrobial Agents and Chemotherapy.

[12]  P. Williams,et al.  Inhibition of biological activities of the aerobactin receptor protein in rough strains of Escherichia coli by polyclonal antiserum raised against native protein. , 1989, Journal of general microbiology.

[13]  S. Gorbach,et al.  In vitro antibacterial activity of bismuth subsalicylate. , 1990, Reviews of infectious diseases.

[14]  M. Manhart.  In vitro antimicrobial activity of bismuth subsalicylate and other bismuth salts. , 1990, Reviews of infectious diseases.

[15]  S. Gorbach,et al.  Effect of bismuth subsalicylate on fecal microflora. , 1990, Reviews of infectious diseases.

[16]  D. Bierer,et al.  Bismuth subsalicylate: history, chemistry, and safety. , 1990, Reviews of infectious diseases.

[17]  D. Heinrichs,et al.  Pyoverdine-mediated iron transport in Pseudomonas aeruginosa: involvement of a high-molecular-mass outer membrane protein. , 1991, FEMS microbiology letters.

[18]  J. E. Arceneaux,et al.  Acquisition of iron from host sources by mesophilic Aeromonas species. , 1991, Journal of general microbiology.

[19]  V. Appanna,et al.  Gallium toxicity and adaptation in Pseudomonas fluorescens. , 1992, FEMS microbiology letters.

[20]  K. Hantke,et al.  Escherichia coli K-12 ferrous iron uptake mutants are impaired in their ability to colonize the mouse intestine. , 1993, FEMS microbiology letters.

[21]  R. Guerrant,et al.  Effect of salicylate, bismuth, osmolytes, and tetracycline resistance on expression of fimbriae by Escherichia coli , 1994, Infection and immunity.