Hypothiocyanite
Hypothiocyanite is the anion [OSCN]− and the conjugate base of hypothiocyanous acid (HOSCN). It is an organic compound part of the thiocyanates as it contains the functional group SCN. It is formed when an oxygen is singly bonded to the thiocyanate group. Hypothiocyanous acid is a fairly weak acid; its dissociation constant is 5.3.
Hypothiocyanite is formed by peroxidase[1] catalysis of hydrogen peroxide and thiocyanate:
- H2O2 + SCN− → OSCN− + H2O
As a bactericide
Hypothiocyanite occurs naturally in the antimicrobial immune system of the human respiratory tract[2] in a redox reaction catalyzed by the enzyme lactoperoxidase.[3] It has been researched extensively for its capabilities as an alternative antibiotic as it is harmless to human body cells while being cytotoxic to bacteria.[4] The exact processes for making hypothiocyanite have been patented as such an effective antimicrobial has many commercial applications.[5]
Mechanism of action
Lactoperoxidase-catalysed reactions yield short lived intermediary oxidation products of SCN−, providing antibacterial activity.[6]
The major intermediary oxidation product is hypothiocyanite OSCN−, which is produced in an amount of about 1 mol per mol of hydrogen peroxide. At the pH optimum of 5.3, the OSCN− is in equilibrium with HOSCN. The uncharged HOSCN is considered to be the greater bactericidal of the two forms.[7] At pH 7, it was evaluated that HOSCN represents 2% compare to OSCN− 98%.[8]
The action of (OSCN)- against bacteria is reported to be caused by sulfhydryls (SH) oxidation.[9]
The oxidation of -SH groups in the bacterial cytoplasmic membrane results in loss of the ability to transport glucose and also in leaking of potassium ions, amino acids and peptide.
OSCN− has also been identified as an antimicrobial agent in milk, saliva,[10] tears, and mucus.
OSCN− is considered as safe product as it is not mutagenic.[11]
Relation to cystic fibrosis
Initially, this particular lactoperoxidase-catalyzed compound was originally discovered while viewing the specific environment of cystic fibrosis patients' weakened respiratory immune system against bacterial infection.[12]
Symptoms of cystic fibrosis include an inability to secrete sufficient quantities of SCN− which results in a shortage of necessary hypothiocyanite, resulting in increasing mucous viscosity, inflammation and bacterial infection in the respiratory tract.
Lactoferrin with hypothiocyanite has been granted orphan drug status by the EMEA[13] and the FDA.[14]
Naturally, the discovery correlated with studies exploring different methods seeking to further gain alternative antibiotics, understanding that most older antibiotics are decreasing in effectiveness against bacteria with antibiotic resistance.
OSCN, which is not an antibiotic, has proved efficacy on superbugs including MRSA reference strains, BCC, Mucoid PA
Schema of LPO/SCN−/H2O2 in human lung
Efficacy range
Non exhaustive list of microorganisms
Bacteria (+Gram, -Gram)
• Acinetobacter species • Aeromonas hydrophila • Bacillus brevis • Bacillus Cereus • Bacillus megaterium • Bacillus subtilis • Burkholderia cepacia • Campylobacter jejuni • Capnocytophaga ochracea • Corynebacterium xerosis • Enterobacter cloacae • Escherichia coli • Haemophilus influenzae • Helicobacter Pylori • Klebsiella oxytoca • Klebsiella pneumoniae • Legionella • Listeria monocytogenes • Micrococcus luteus • Mycobacterium smegmatis • Mycobacterium abscessus • Neisseria species • Pseudomonas aeruginosa • Pseudomonas pyocyanea • Salmonella species • Selenomonas sputigena • Shigella sonnei • Staphylococcus aerogenes • Staphylococcus Aureus • Streptococcus agalactiae • Streptococcus faecalis • Streptococcus mutans • Wolinella recta • Xanthomonas campestris • Yersinia enterocolitica
Virus[15]
• Herpes simplex virus, HSV • Immunodeficient virus, HIV • Respiratory Syncytial virus, RSV • Echovirus 11 • Influenza virus
Yeast and mould
• Candida albicans • Aspergillus niger • Colletotrichum musae • Colletotrichum gloeosporioide • Botryodiplodia theobromae • Fusarium monoliforme • Fusarium oxysporum • Rhodotula rubra • Byssochlamys fulva • Sclerotinia
See also
References
- ↑ Furtmüller PG, Zederbauer M, Jantschko W, Helm J, Bogner M, Jakopitsch C, Obinger C (January 2006). "Active site structure and catalytic mechanisms of human peroxidases". Arch. Biochem. Biophys. 445 (2): 199–213. PMID 16288970. doi:10.1016/j.abb.2005.09.017.
- ↑ Al Obaidi AH (July 2007). "Role of airway lactoperoxidase in scavenging of hydrogen peroxide damage in asthma". Ann Thorac Med. 2 (3): 107–10. PMC 2732085
. PMID 19727356. doi:10.4103/1817-1737.33698. - ↑ Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (January 2007). "A Novel Host Defense System of Airways Is Defective in Cystic Fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83. PMC 2720149 . PMID 17082494. doi:10.1164/rccm.200607-1029OC.
- ↑ Carlsson J, Edlund MB, Hänström L (June 1984). "Bactericidal and cytotoxic effects of hypothiocyanite-hydrogen peroxide mixtures". Infect. Immun. 44 (3): 581–6. PMC 263633 . PMID 6724690.
- ↑ Mansson-Rahemtulla B, Pruitt KM, Tenovuo J, Le TM (October 1983). "A mouthrinse which optimizes in vivo generation of hypothiocyanite". J. Dent. Res. 62 (10): 1062–6. PMID 6578235. doi:10.1177/00220345830620101101.
- ↑ Pruitt KM, Tenovuo J, Andrews RW, McKane T (February 1982). "Lactoperoxidase-catalyzed oxidation of thiocyanate: polarographic study of the oxidation products". Biochemistry. 21 (3): 562–7. PMID 7066307. doi:10.1021/bi00532a023.
- ↑ Thomas EL, Pera KA, Smith KW, Chwang AK (February 1983). "Inhibition of Streptococcus mutans by the lactoperoxidase antimicrobial system". Infect. Immun. 39 (2): 767–78. PMC 348016 . PMID 6832819.
- ↑ Thomas EL (May 1981). "Lactoperoxidase-catalyzed oxidation of thiocyanate: equilibria between oxidized forms of thiocyanate". Biochemistry. 20 (11): 3273–80. PMID 7248282. doi:10.1021/bi00514a045.
- ↑ Thomas EL, Aune TM (May 1978). "Lactoperoxidase, peroxide, thiocyanate antimicrobial system: correlation of sulfhydryl oxidation with antimicrobial action". Infect. Immun. 20 (2): 456–63. PMC 421877 . PMID 352945.
- ↑ Tenovuo J (January 2002). "Clinical applications of antimicrobial host proteins lactoperoxidase, lysozyme and lactoferrin in xerostomia: efficacy and safety". Oral Dis. 8 (1): 23–9. PMID 11936452. doi:10.1034/j.1601-0825.2002.1o781.x.
- ↑ White WE, Pruitt KM, Mansson-Rahemtulla B (February 1983). "Peroxidase-Thiocyanate-Peroxide Antibacterial System Does Not Damage DNA". Antimicrob. Agents Chemother. 23 (2): 267–72. PMC 186035 . PMID 6340603. doi:10.1128/aac.23.2.267.
- ↑ Gattas MV, Forteza R, Fragoso MA, Fregien N, Salas P, Salathe M, Conner GE (November 2009). "OXIDATIVE EPITHELIAL HOST DEFENSE IS REGULATED BY INFECTIOUS AND INFLAMMATORY STIMULI". Free Radic. Biol. Med. 47 (10): 1450–8. PMC 2767478 . PMID 19703552. doi:10.1016/j.freeradbiomed.2009.08.017.
- ↑ "Public summary of positive opinion for orphan designation of hypothiocyanite / lactoferrin for the treatment of cystic fibrosis" (PDF). Pre-authorisation Evaluation of Medicines for Human Use. European Medicines Agency. 2009-09-07. Retrieved 2010-01-23.
- ↑ "Meveol: orphan drug status granted by the FDA for the treatment of cystic fibrosis". United States Food and Drug Administration. 2009-11-05. Retrieved 2010-01-23.
- ↑ Mikola H, Waris M, Tenovuo J. Inhibition of herpes simplex virus type 1, respiratory syncytial virus and echovirus type 11 by peroxidase-generated hypothiocyanite. Antiviral Res. 1995 Mar;26(2):161-71
Further reading
- Childers M, Eckel G, Himmel A, Caldwell J (2007). "A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates". Med. Hypotheses. 68 (1): 101–12. PMID 16934416. doi:10.1016/j.mehy.2006.06.020.
- Conner GE, Salathe M, Forteza R (December 2002). "Lactoperoxidase and hydrogen peroxide metabolism in the airway". Am. J. Respir. Crit. Care Med. 166 (12 Pt 2): S57–61. PMID 12471090. doi:10.1164/rccm.2206018.
- Conner GE, Wijkstrom-Frei C, Randell SH, Fernandez VE, Salathe M (January 2007). "The Lactoperoxidase System Links Anion Transport To Host Defense in Cystic Fibrosis". FEBS Lett. 581 (2): 271–8. PMC 1851694 . PMID 17204267. doi:10.1016/j.febslet.2006.12.025.
- Eastvold JS (2005). "Hypothiocyanous Acid: An Overview" (PDF). Free Radical Biology and Medicine.
- Minarowski Ł, Sands D, Minarowska A, Karwowska A, Sulewska A, Gacko M, Chyczewska E (2008). "Thiocyanate concentration in saliva of cystic fibrosis patients". Folia Histochem. Cytobiol. 46 (2): 245–6. PMID 18519245. doi:10.2478/v10042-008-0037-0.
- Rada B, Leto TL (2009). "Redox warfare between airway epithelial cells and Pseudomonas: Dual oxidase versus pyocyanin". Immunol. Res. 43 (1–3): 198–209. PMC 2776630 . PMID 18979077. doi:10.1007/s12026-008-8071-8.
- Conner GE, Salathe M, Forteza R (December 2002). "Lactoperoxidase and hydrogen peroxide metabolism in the airway". Am. J. Respir. Crit. Care Med. 166 (12 Pt 2): S57–61. PMID 12471090. doi:10.1164/rccm.2206018.
- Fischer H (October 2009). "Mechanisms and Function of DUOX in Epithelia of the Lung". Antioxid. Redox Signal. 11 (10): 2453–65. PMC 2823369 . PMID 19358684. doi:10.1089/ARS.2009.2558.
- Kussendrager KD, van Hooijdonk AC (November 2000). "Lactoperoxidase: physico-chemical properties, occurrence, mechanism of action and applications". Br. J. Nutr. 84 Suppl 1: S19–25. PMID 11242442. doi:10.1017/S0007114500002208.
- Pedemonte N, Caci E, Sondo E, Caputo A, Rhoden K, Pfeffer U, Di Candia M, Bandettini R, Ravazzolo R, Zegarra-Moran O, Galietta LJ (April 2007). "Thiocyanate transport in resting and IL-4-stimulated human bronchial epithelial cells: role of pendrin and anion channels". J. Immunol. 178 (8): 5144–53. PMID 17404297. doi:10.4049/jimmunol.178.8.5144.
- Rada B, Leto TL (2009). "Redox warfare between airway epithelial cells and Pseudomonas: Dual oxidase versus pyocyanin". Immunol. Res. 43 (1–3): 198–209. PMC 2776630 . PMID 18979077. doi:10.1007/s12026-008-8071-8.
- Rada B, Leto TL (2008). "Oxidative innate immune defenses by Nox/Duox family NADPH Oxidases". Contrib Microbiol. Contributions to Microbiology. 15: 164–87. ISBN 978-3-8055-8548-4. PMC 2776633 . PMID 18511861. doi:10.1159/000136357.
- Reiter B, Härnulv G (1984). "Lactoperoxidase antibacterial system natural occurrence, biological functions and practical applications". J Food Prot. 47: 724–732.
- Shin K, Wakabayashi H, Yamauchi K, Teraguchi S, Tamura Y, Kurokawa M, Shiraki K (August 2005). "Effects of orally administered bovine lactoferrin and lactoperoxidase on influenza virus infection in mice". J. Med. Microbiol. 54 (Pt 8): 717–23. PMID 16014423. doi:10.1099/jmm.0.46018-0.
- Thomas EL, Bates KP, Jefferson MM (September 1980). "Hypothiocyanite ion: detection of the antimicrobial agent in human saliva". J. Dent. Res. 59 (9): 1466–72. PMID 6931123. doi:10.1177/00220345800590090201.
- Wijkstrom-Frei C, El-Chemaly S, Ali-Rachedi R, Gerson C, Cobas MA, Forteza R, Salathe M, Conner GE (August 2003). "Lactoperoxidase and human airway host defense". Am. J. Respir. Cell Mol. Biol. 29 (2): 206–12. PMID 12626341. doi:10.1165/rcmb.2002-0152OC.
- Xu Y, Szép S, Lu Z (December 2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515–9. Bibcode:2009PNAS..10620515X. PMC 2777967 . PMID 19918082. doi:10.1073/pnas.0911412106.