Journal of eISSN: 2373-437X JMEN

Microbiology & Experimentation
Volume 2 Issue 3 - 2015
Bismuth Thiols as Anti-Biofilm Agents
Phil Domenico*
Senior Scientist, Microbion Biosciences, USA
Received: August 4, 2015| Published: August 5, 2015
*Corresponding author: Phil Domenico, Senior Scientist, Microbion Biosciences, New York, NY 10025, USA, E-mail: @
Citation: Domenico P (2015) Bismuth Thiols as Anti-Biofilm Agents. J Microbiol Exp 2(3): 00049.DOI: 10.15406/jmen.2015.02.00049


Bismuth thiols (BTs) are antimicrobial agents with great potential to prevent and treat biofilms.  The active ingredient in BTs is bismuth- a popular, over-the-counter, antimicrobial agent (e.g., Pepto-Bismol®), which exhibits anti-biofilm properties, likely by inhibiting exopolysaccharides (EPS)- the biofilm matrix in most bacteria [1]. Bismuth appears to interfere with iron transport/metabolism [2], which is essential for ATP production and, in turn, EPS synthesis.

The other halves of BT’s are thiols-small, sulfhydryl-containing, organic molecules. Natural thiols include methionine, cysteine and ∝-lipoic acid, which interact with iron, zinc and other metal-cofactors for enzyme function, immune surveillance, detoxification, and protein structure. Medically, thiols are employed as chelating agents and antidotes for heavy metal poisoning [3]. However, only lipophilic thiols potentiate bismuth antimicrobial activity, some by several orders of magnitude. Lipophilic thiols not only solubilize bismuth, but also allow it to traverse biological membranes to help reach its target [4]. BTs likely interfere with iron transport and redox enzymes involved in EPS expression, via thiol exchange [5].

The combination of bismuth and thiol (preferably dithiol) produces a potent, broad-spectrum antimicrobial agent with diverse properties, depending on the thiol employed. The simplest and most potent BT is bismuth ethanedithiol (BisEDT). However, each thiol has unique biological properties: whether bacteriostatic or bactericidal; acidic or alkaline; hydrophilic or hydrophobic; and anti-bacterial, anti-fungal [6], or even anti-viral activity. Rather than a single drug, BTs are a versatile family of agents.

BTs show potent antimicrobial activity against a wide range of bacteria [7]. At sub-inhibitory concentrations (≤1µg/mL), BTs prevent biofilm formation in methicillin-resistant Staphylococcus aureus (MRSA) [8] and Pseudomonas aeruginosa [9-11]. Subinhibitory BTs inhibited EPS production in Klebsiella pneumoniae by over 90%, which drastically increased uptake and killing by white blood cells [12].

In animal models, BT-coated grafts inserted subcutaneously into rats, then contaminated with MRSA, disallowed build-up of bacteria on graft surfaces [13]. BTs significantly decreased adherence of several bacterial pathogens on the surface of stents [14]. Intratracheal administration in rats with liposomal BT-tobramycin reduced pulmonary P. aeruginosa infection significantly [15]. When administrated locally to infected open fracture wounds, BTs prevented S. aureus biofilm formation, disrupted preexisting biofilm and sensitized bacteria to antibiotic treatment and immune defenses [16]. Several antibiotics were potentiated in combination with sub-MIC BTs [17], even against highly-resistant Burkholderia strains [18].

BisEDT is now poised to begin Phase 2 clinical studies. It has been granted FDA Qualified Infectious Disease Product (QIDP) status for treatment of serious, life- or limb- threatening infections associated with orthopedic implants and chronic wounds. New antimicrobial/anti-biofilm therapies for serious lung infections and for biodefense are underway.

By virtue of enhancing antibiotics, reducing virulence, and fostering immune defenses at low, nontoxic concentrations- without inducing bacterial resistance-BTs may address many unmet needs in medicine. BTs are expected to safely and effectively treat antibiotic-resistant infections, including those from MRSA, VRE, resistant Gram-negative bacteria, TB, bioterrorism agents, and many other bacteria. They also hold promise as environmentally responsible solutions to the problem of biofouling in industrial processes [19,20].


  1. Domenico P, Landolphi DR, Cunha BA (1991) Reduction of capsular polysaccharides and potentiation of aminoglycoside inhibition in gram-negative bacteria with bismuth subsalicylate. J Antimicrob Chemother 28(6): 801-810.
  2. Domenico P, Reich J, Madonia W, Cunha BA (1996) Resistance to bismuth among gram-negative bacteria is dependent upon iron and its uptake. J Antimicrob Chemother 38(6): 1031-1040.
  3. Flora SJ, Pachauri V (2010) Chelation in Metal Intoxication. Int J Environ Res Public Health 7(7): 2745-2788.
  4. Mahony DE, Lim-Morrison S, Bryden L, Faulkner G, Hoffman PS, et al. (1999) Antimicrobial activities of synthetic bismuth compounds against Clostridium difficile. Antimicrob Agents Chemother 43(3): 582-588.
  5. Phillips HA, Burford N (2008) Identification of bismuth-thiolate-carboxylate clusters
    by electrospray ionization mass spectrometry. Inorg Chem 47(7): 2428-2441.
  6. Domenico P, Cunha CB, Vaysman D, Krom BP, Cihlar RL, et al. (2005) Pyrithione enhanced antimicrobial activity of bismuth. Antibiotics Clinicians 9: 291-297.
  7. Domenico P, Salo RJ, Novick SG, Schoch PE, Van Horn K, Cunha BA (1997) Enhancement of bismuth antibacterial activity with lipophilic thiol chelators. Antimicrob Agents Chemother 41(8): 1697-1703.
  8. Domenico P, Baldassarri L, Schoch PE, Kaehler K, Sasatsu M, et al. (2001) Activities of bismuth thiols against staphylococci and staphylococcal biofilms. Antimicrob Agents Chemother 45(5): 1417-1421.
  9. Folsom, JP, Baker B, Stewart PS (2011) In vitro efficacy of bismuth thiols against biofilms formed by bacteria isolated from human chronic wounds. J Applied Microbiol 111(4): 989-996.
  10. Huang CT, Stewart PS (1999) Reduction of polysaccharide production in Pseudomonas aeruginosa biofilms by bismuth dimercaprol (BisBAL) treatment. J Antimicrob Chemother 44(5): 601-605.
  11. Wu CL, Domenico P, Hassett DJ, Beveridge T, Hauser A, et al. (2002) Subinhibitory bismuth thiols reduce virulence of Pseudomonas aeruginosa. American J Respir Cell Mol Biol 26(6): 731-738.
  12. Domenico P, Tomas JM, Merino S, Rubires X, Cunha BA (1999) Surface antigen exposure by bismuth-dimercaprol suppression of Klebsiella pneumoniae capsular polysaccharide. Infect Immun 67(2): 664-669.
  13. Domenico P, Gurzenda E, Giacometti A, Cirioni O, Ghiselli R, et al. (2004) BisEDT and RIP act in synergy to prevent graft infections by resistant staphylococci. Peptides 25(12): 2047-2053.
  14. Zhang H, Tang J, Meng X, Tsang J, Tsang TK (2005) Inhibition of bacterial adherence on the surface of stents and bacterial growth in bileby bismuth dimercaprol. Digestive Dis Sci 50(6): 1046-1051.
  15. Alhariri M, Omri A (2013) Efficacy of liposomal bismuth-ethanedithiol-loaded tobramycin after intratracheal administration in rats with pulmonary Pseudomonas aeruginosa infection. Antimicrob Agents Chemother 57(1): 569-578.
  16. Penn-Barwell, JG, Baker B, Wenke JC (2015) Local bismuth thiols potentiate antibiotics and reduce infection in a contaminated open fracture model. J Orthopaedic Trauma 29(2): e73-e78.
  17. Domenico P, Kazzaz JA, Davis JM (2003) Combating antibiotic resistance with bismuth-thiols. Res Advances Antimicrob Agents Chemother 3: 79-85.
  18. Veloira WG, Gurzenda EM, Domenico P, Davis JM, Gurzenda E, et al. (2003) In vitro activity and synergy of bismuth thiols and tobramycin against Burkholderia cepacia complex. J Antimicrob Chemother 52(6): 915-919.
  19. Badireddy AR, Chellam S (2011) Bismuth dimercaptopropanol (BisBAL) inhibits formation of multispecies wastewater flocs. J Applied Microbiol 110(6): 1426-1437.
  20. Codony F, Domenico P, Mas J (2003) Assessment of bismuth thiols and conventional disinfectants on drinking water biofilms. J Applied Microbiol 95(2): 288-293.
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