Boromycin

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Boromycin
Boromycin.png
Clinical data
ATC code
  • none
Identifiers
  • [1-{(1R)-1-[(1R,2R,5S,6R,8R,12R,14S,17R,18R,22S,24Z,28S,30S,33R)-12,28-Dihydroxy-1,2,18,19-tetra(hydroxy-κO)-6,13,13,17,29,29,33-heptamethyl-3,20-dioxo-4,7,21,34,35-pentaoxatetracyclo[28.3.1.15,8.114,18]hexatriacont-24-en-22-yl]ethoxy}-3-methyl-1-oxo-2-butanaminiumato(4-)]boron
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
Chemical and physical data
Formula C45H74BNO15
Molar mass 879.89 g·mol−1
3D model (JSmol)
  • CC(C)C([NH3+])C(=O)O[C@H](C)[C@H]7OC(=O)C4O[B-]25O[C@@H](C(=O)O[C@H]1C[C@H](O[C@@H]1C)CCC[C@@H](O)C(C)(C)[C@@H]3CC[C@@H](C)[C@@]4(O2)O3)[C@]6(O5)O[C@@H](CC[C@H]6C)C(C)(C)[C@@H](O)CC\C=C/C7
  • InChI=1S/C45H73BNO15/c1-24(2)36(47)39(50)54-27(5)30-16-12-11-13-17-32(48)42(7,8)34-21-19-26(4)45(57-34)38-41(52)56-31-23-29(53-28(31)6)15-14-18-33(49)43(9,10)35-22-20-25(3)44(58-35)37(40(51)55-30)59-46(60-38,61-44)62-45/h11-12,24-38,48-49H,13-23,47H2,1-10H3/q-1/p+1/b12-11-/t25-,26-,27-,28-,29-,30+,31+,32+,33-,34+,35+,36?,37?,38+,44+,45+,46?/m1/s1 Yes check.svgY
  • Key:OOBFYEMEQCZLJL-WIHWYPJVSA-O Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Boromycin is a bacteriocidal polyether-macrolide antibiotic. It was initially isolated from the Streptomyces antibioticus , and is notable for being the first natural product found to contain the element boron. It is effective against most Gram-positive bacteria, but is ineffective against Gram-negative bacteria. Boromycin kills bacteria by negatively affecting the cytoplasmic membrane, resulting in the loss of potassium ions from the cell. Boromycin has not been approved as a drug for medical use.

Contents

Discovery

Boromycin was discovered by the scholars of the Institute for Special Botany and Organic Chemical Laboratories at the Swiss Federal Institute of Technology, Zurich, Switzerland, who, in 1967, published a study [1] in as an article called "Metabolic products of microorganisms" in the Helvetica Chimica Acta journal. In this article, the authors described that a new strain of Streptomyces antibioticus produces a novel antibiotic which was the first boron-containing organic compound found in nature. The authors called this new compound boromycin and characterized it as a complex of boric acid with a tetradentate organic complexing agent that yields by hydrolysis D-valine, boric acid, and a polyhydroxy compound of macrolide type. [1]

General information

Boromycin has potential medical uses as an antibiotic for treating Gram-positive bacterial infections, coccidiosis, and certain protozoal infections, but its efficacy and safety in clinical settings were not determined. [2] Boromycin has not been approved as a drug for medical use in the USA (by the FDA), Europe, Canada, Japan, Russia, China, or the former Soviet Union.

Boromycin is a boron-containing compound produced by Streptomyces antibioticus, isolated from the soil of Ivory Coast. It exhibits antimicrobial properties, inhibiting the growth of Gram-positive bacteria while having no effect on certain Gram-negative bacteria and fungi. Boromycin has also shown activity against protozoa of the genera plasmodiae and babesiae. [2]

In addition to its antimicrobial effects, boromycin has been studied to treat and prevent coccidiosis in susceptible poultry. [3] It has been predicted to inhibit the replication of HIV-1 [4] and the synthesis of proteins, RNA, and DNA in whole cells of Bacillus subtilis. Boromycin binds to the cytoplasmic membrane within the cell and is antagonized by surface-active compounds. It is bound to lipoprotein and does not influence the K+, Na+-ATPase of the cytoplasmic membrane. [2]

The removal of boric acid from the boromycin molecule leads to a loss of antibiotic activity. There are minor products of boromycin fermentation, differing in the acylation position. Experiments with feeding the production strain Sorangium cellulosum with specific isotopes have shed light on the biosynthesis of tartrolons, which are closely related to boromycin and aplasmomycin. [2]

Research

Boron, the essential trace element found in boromycin, benefits plants, animals, and humans. Boron-containing compounds such as boromycin have gained attention for their potential medicinal applications. [2]

Researchers are exploring the incorporation of boron into biologically active molecules, including for boron neutron capture therapy of brain tumors. [5] The role of the boron atom in neutron capture therapy for malignant brain tumors is to target tumor cells selectively. When a non-radioactive boron isotope (10B) is administered and accumulates in tumor cells, these cells can be selectively destroyed when irradiated with low-energy thermal neutrons. The collision of neutrons with 10B releases high linear energy transfer particles, such as α-particles and lithium-7 nuclei, which can selectively destroy the tumor cells while sparing surrounding normal cells. [5]

Some boron-containing biomolecules may also act as signaling molecules interacting with cell surfaces. [2]

Anti-HIV activity

A 1996 study suggests that boromycin has anti-HIV activity in in vitro laboratory experiments. In that study, boromycin inhibited the replication of both clinically isolated HIV-1 strains and cultured strains. The mechanism of action was believed to involve blocking the later stage of HIV infection, specifically the maturity step for replication of the HIV molecule. [4]

While the study provides promising results in a controlled laboratory setting, it is important to note that in vitro experiments do not always accurately predict the effectiveness of a compound in living organisms. Strong evidence should be accumulated to determine boromycin's actual in vivo anti-HIV activity in a living human organism. Accumulating such evidence typically involves preclinical studies in animal models to assess safety, efficacy, and pharmacokinetics before progressing to clinical trials in humans. [6] [7]

The lack of replication of the 1996 study's [4] findings by other studies suggests a lack of confirmation regarding the anti-HIV activity of boromycin. This could be due to potential methodological limitations in the original study, such as variations in experimental conditions or difficulties in isolating and purifying boromycin. It is also possible that the initial study produced a false positive result, where the observed anti-HIV activity resulted from chance or experimental artifacts rather than a true effect. Additionally, publication bias may play a role, as positive or novel findings are more likely to be published, potentially leading to an incomplete picture of the overall research on boromycin's anti-HIV activity. Studies are needed to address these factors and determine the true effectiveness of boromycin as an in vivo anti-HIV agent. [8] [9] [10] [11]

Anti-plasmodium activity

In a 2021 study, [12] boromycin showed activity against Plasmodium falciparum and Plasmodium knowlesi, two species of malaria parasites. It demonstrated rapid killing of asexual stages of both species, including multidrug-resistant strains, at low concentrations. Additionally, boromycin exhibited activity against Plasmodium falciparum stage V gametocytes. However, other studies have not confirmed these results and should be interpreted cautiously. Additional scientific investigation and validation are required to establish the efficacy of boromycin as a potential antimalarial candidate. It is essential to conduct further studies to confirm and substantiate the findings, ensuring reliable and reproducible results. The potential of boromycin in the context of malaria treatment warrants continued research and rigorous examination to assess its effectiveness and potential implications for therapeutic applications fully. [13]

Activity against intracellular protozoal parasites

A 2021 study [3] by scholars from Central Luzon State University, Philippines, and Washington State University, USA, showed the activity of boromycin against Toxoplasma gondii and Cryptosporidium parvum, which are intracellular protozoal parasites affecting humans and animals. The study found that boromycin effectively inhibited the intracellular proliferation of both parasites at low concentrations. However, these preliminary results have not yet been confirmed by further studies. To validate the results and understand the potential of boromycin as a therapeutic option for the treatment of toxoplasmosis and cryptosporidiosis, it is critical to conduct studies to confirm the activity of boromycin against intracellular protozoan parasites in living host organisms. [3]

Related Research Articles

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References

  1. 1 2 Hütter R, Keller-Schierlein W, Knüsel F, Prelog V, Rodgers GC, Suter P, et al. (January 1967). "[The metabolic products of microorganisms. Boromycin]". Helvetica Chimica Acta. 50 (6): 1533–1539. doi:10.1002/hlca.19670500612. PMID   6081908.
  2. 1 2 3 4 5 6 Rezanka T, Sigler K (February 2008). "Biologically active compounds of semi-metals". Phytochemistry. 69 (3): 585–606. Bibcode:2008PChem..69..585R. doi:10.1016/j.phytochem.2007.09.018. PMID   17991498.
  3. 1 2 3 Abenoja J, Cotto-Rosario A, O'Connor R (March 2021). "Boromycin Has Potent Anti-Toxoplasma and Anti-Cryptosporidium Activity". Antimicrobial Agents and Chemotherapy. 65 (4). doi:10.1128/AAC.01278-20. PMC   8097477 . PMID   33468470.
  4. 1 2 3 Kohno J, Kawahata T, Otake T, Morimoto M, Mori H, Ueba N, et al. (June 1996). "Boromycin, an anti-HIV antibiotic". Bioscience, Biotechnology, and Biochemistry. 60 (6): 1036–1037. doi: 10.1271/bbb.60.1036 . PMID   8695905.
  5. 1 2 Miyatake SI, Wanibuchi M, Hu N, Ono K (August 2020). "Boron neutron capture therapy for malignant brain tumors". Journal of Neuro-Oncology. 149 (1): 1–11. doi:10.1007/s11060-020-03586-6. hdl: 2433/226821 . PMID   32676954. S2CID   220577322.
  6. ↑ Chien JY, Friedrich S, Heathman MA, de Alwis DP, Sinha V (October 2005). "Pharmacokinetics/Pharmacodynamics and the stages of drug development: role of modeling and simulation". The AAPS Journal. 7 (3): E544–E559. doi:10.1208/aapsj070355. PMC   2751257 . PMID   16353932.
  7. ↑ Mead S, Tagliavini F (2018). "Clinical trials". Human Prion Diseases. Handbook of Clinical Neurology. Vol. 153. Elsevier. pp. 431–444. doi:10.1016/B978-0-444-63945-5.00024-6. ISBN   9780444639455. PMID   29887150.
  8. ↑ Mehta M, Schug B, Blume HH, Beuerle G, Jiang W, Koenig J, et al. (November 2023). "The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference". European Journal of Pharmaceutical Sciences. 190: 106566. doi: 10.1016/j.ejps.2023.106566 . PMID   37591469. S2CID   260943533.
  9. ↑ Lee J, Gong Y, Bhoopathy S, DiLiberti CE, Hooker AC, Rostami-Hodjegan A, et al. (November 2021). "Public Workshop Summary Report on Fiscal Year 2021 Generic Drug Regulatory Science Initiatives: Data Analysis and Model-Based Bioequivalence". Clinical Pharmacology and Therapeutics. 110 (5): 1190–1195. doi:10.1002/cpt.2120. PMID   33236362. S2CID   227165142.
  10. ↑ Pepin XJ, Dressman J, Parrott N, Delvadia P, Mitra A, Zhang X, et al. (February 2021). "In Vitro Biopredictive Methods: A Workshop Summary Report". Journal of Pharmaceutical Sciences. 110 (2): 567–583. doi: 10.1016/j.xphs.2020.09.021 . PMID   32956678. S2CID   221842404.
  11. ↑ Kitaeva KV, Rutland CS, Rizvanov AA, Solovyeva VV (2020). "Cell Culture Based in vitro Test Systems for Anticancer Drug Screening". Frontiers in Bioengineering and Biotechnology. 8: 322. doi: 10.3389/fbioe.2020.00322 . PMC   7160228 . PMID   32328489.
  12. ↑ de Carvalho LP, Groeger-Otero S, Kreidenweiss A, Kremsner PG, Mordmüller B, Held J (2021). "Boromycin has Rapid-Onset Antibiotic Activity Against Asexual and Sexual Blood Stages of Plasmodium falciparum". Frontiers in Cellular and Infection Microbiology. 11: 802294. doi: 10.3389/fcimb.2021.802294 . PMC   8795978 . PMID   35096650.
  13. ↑ Kumar V, Bhargava G (2022). "Editorial: Protozoal infections: Treatment and challenges". Frontiers in Cellular and Infection Microbiology. 12: 1002602. doi: 10.3389/fcimb.2022.1002602 . PMC   9471550 . PMID   36118046.
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