Natamycin

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Natamycin
Eye drops[1]
ATC code)
Identifiers
  • (1R,3S,5R,7R,8E,12R,14E,16E,18E,20E,22R,24S,25R,26S)-22-[(3-amino-3,6-dideoxy-D-mannopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28-trioxatricyclo[22.3.1.05,7]octacosa-8,14,16,18,20-pentaene-25-carboxylic acid
JSmol)
Density1.35 g/ml g/cm3
Melting pointDarkens at ±200 °C with vigorous decomposition at 280-300 °C
Solubility in water0.39 mg/ml
  • OC(=O)[C@@H]3[C@@H](O)C[C@@]2(O)C[C@@H](O)C[C@H]4O[C@@H]4/C=C/C(=O)O[C@H](C)C\C=C\C=C\C=C\C=C\[C@H](O[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O)C[C@@H]3O2
  • InChI=1S/C33H47NO13/c1-18-10-8-6-4-3-5-7-9-11-21(45-32-30(39)28(34)29(38)19(2)44-32)15-25-27(31(40)41)22(36)17-33(42,47-25)16-20(35)14-24-23(46-24)12-13-26(37)43-18/h3-9,11-13,18-25,27-30,32,35-36,38-39,42H,10,14-17,34H2,1-2H3,(H,40,41)/b4-3+,7-5+,8-6+,11-9+,13-12+/t18-,19-,20+,21+,22+,23-,24-,25+,27-,28+,29-,30+,32+,33-/m1/s1
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  • Key:NCXMLFZGDNKEPB-FFPOYIOWSA-N

Natamycin, also known as pimaricin, is an

eyedrops.[1] Natamycin is also used in the food industry as a preservative.[2]

Natamycin was discovered in 1955 and approved for medical use in the United States in 1978.[1][2] It is on the World Health Organization's List of Essential Medicines.[3] It is produced by fermentation of certain types of the bacterium Streptomyces.[1][4]

Uses

Medical

Natamycin is used to treat fungal infections, including

oral thrush.[6]

Food

Natamycin has been used for decades in the food industry as a hurdle to fungal outgrowth in dairy products and other foods. Potential advantages for the usage of natamycin might include the replacement of traditional chemical preservatives, a neutral flavor impact, and less dependence on pH for efficacy, as is common with chemical preservatives. It can be applied in a variety of ways: as an aqueous suspension (such as mixed into a brine) sprayed on the product or into which the product is dipped, or in powdered form (along with an anticaking agent such as cellulose) sprinkled on or mixed into the product.[citation needed]

While not currently approved for use on meats in the United States, some countries allow natamycin to be applied to the surface of dry and fermented sausages to prevent mold growth on the casing. Also, natamycin is approved for various dairy applications in the United States. More specifically, natamycin is commonly used in products such as cream cheeses, cottage cheese, sour cream, yogurt, shredded cheeses, cheese slices, and packaged salad mixes. One of the reasons for food producers to use natamycin is to replace the artificial preservative sorbic acid.[7] Natamycin is also known to diffuse slower and lesser into cheese when compared to sorbate, which could otherwise cause undesirable changes to the flavor.[8]

As a food additive, it has E number E235. Throughout the European Union, it is approved only as a surface preservative for certain cheese and dried sausage products. It must not be detectable 5 mm below the rind. While natamycin is approved in different applications at different levels in the world, it is approved in over 150 countries worldwide.[9]

The European Food Safety Authority (EFSA) panel took over the responsibilities of providing scientific food safety advice to the EU from the Scientific Committee on Food in 2002.[10] In 2009, the EFSA considered the proposed use levels of natamycin are safe if it is used for the surface treatment for these cheese and sausage types.[11]

Safety

Natamycin does not have

metabolites of natamycin also lack toxicity. The breakdown products of natamycin under various storage conditions may have a lower LD50 than natamycin, but in all cases, the numbers are quite high. In humans, a dose of 500 mg/kg/day repeated over multiple days caused nausea, vomiting, and diarrhea.[13]

No evidence shows natamycin, at either pharmacological levels or levels encountered as a food additive, can harm normal

intestinal flora, but definitive research may not be available.[13] However, some people are allergic to natamycin.[14]

The EFSA has concluded that the use of natamycin as a food additive has no relevant risk for the development of

Mechanism of action

Natamycin inhibits the growth of fungi by specifically binding to ergosterol present in fungal cell membranes. Natamycin inhibits amino acid and glucose transport proteins leading to a loss of nutrient transport across the plasma membrane. While this binding is reversible, ergosterol binding acts as a universal mechanism of fungal inhibition, allowing natamycin to act on diverse fungal pathogens from Saccharomyces yeast to Aspergillus moulds. Natamycin is unique amongst related antifungals specifically because it does not directly cause membrane permeabilization.[15][16][17] Structurally-related antibiotics with similar binding properties are thought to produce hydrophilic channels that allow leakage of potassium and sodium ions from the cell.[18]

Natamycin has very low solubility in water; however, natamycin is effective at very low levels. Its

ppm for most molds.[citation needed
]

Biochemistry

Natamycin is produced as a secondary metabolite by some Streptomyces species: S. natalensis, S. lydicus, S. chattanoogensis and S. gilvosporeus.[4] Structurally, its core is a macrolide containing a polyene segment, with carboxylic acid and mycosamine groups attached. As with other polyene antimycotics, the biosynthesis begins with a series of polyketide synthase modules, followed by additional enzymatic processes for oxidation and attachment of the substituents.[19]

Natamycin is produced on an industrial scale by fermentation of various Streptomyces strains, including S. chattanoogensis L10.[19]

History

Natamycin was first isolated in 1955 from fermentation broth of a Streptomyces natalensis cell culture.[20] It was originally named pimaricin to honor Pietermaritzburg, where Streptomyces natalensis was acquired. Pimaricin was later renamed after the World Health Organization (WHO) mandated that antibiotics produced by Streptomyces end in –mycin. The name natamycin was chosen in reference to the natalensis species name.[20]

Society and culture

Natamycin appears on

Whole Foods' "Unacceptable Ingredients for Food" list.[21]

References

  1. ^ a b c d e f g h i j "Natamycin". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  2. ^ .
  3. . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  4. ^ .
  5. .
  6. ^ "Topical Antifungal Drugs: Natamycin". Virginia-Maryland Regional College of Veterinary Medicine. Archived from the original on 7 April 2017.)
  7. ^ "Kraft Singles Ditch Artificial Preservatives". NBC News. 11 February 2014. Archived from the original on 8 October 2022.
  8. S2CID 257086547
    .
  9. ^ "Regulatory and Approval Information". Natamycin.com.
  10. ^ "Safety and regulation: the formal process for analyzing the test data on food additives". understandingfoodadditives.org. Archived from the original on 7 January 2014.
  11. ^ .
  12. .
  13. ^ a b Mattia A, Dr Cerniglia C, Baines J. Safety evaluation of certain food additives and contaminants: natamicin (pimaricin). WHO Food Additives Series #48 (Report). International Programme on Chemical Safety (IPCS).
  14. ^ "Natamycin". RxList.
  15. PMID 18165687
    .
  16. .
  17. .
  18. .
  19. ^ .
  20. ^ a b "The origins of natamycin". Archived from the original on 16 July 2014. Natamycin was isolated for the first time in 1955 in the Gist-brocades research laboratories, from the fermentation broth of a culture of Streptomyces natalensis.
  21. ^ "Unacceptable Ingredients for Food". Whole Foods Market IP. L.P. Archived from the original on 2 January 2018.