Miramistin – developed for the Soviet Space Program – can kill drug-resistant germs, viruses, coronaviruses, adenoviruses, and human immunodeficiency virus (HIV)

0
224

A little-known non-toxic antiseptic developed in the Soviet Union during the Cold War has enormous potential to beat common infections, say University of Manchester scientists.

Miramistin, developed for the Soviet Space Program and little known in the West, can inhibit or kill influenza A, human papilloma viruses that cause warts, coronaviruses, adenoviruses, and human immunodeficiency virus (HIV).

The potion is much less toxic to human cells than conventional antiseptics such as cyclohexamide and cetylpyridinium chloride, and is also biodegradable.

It can be used against Candida and Aspergillus species, and also kills bacteria, including Stарhуlососсus, Proteus and Klebsiella as well as the bugs that cause syphilis and gonorrhea.

Miramistin is still used in some of the former countries of the Soviet Bloc in hospitals and surgeries, mainly to treat to treat wounds and ulcers.

However, it is barely known elsewhere and there is almost no mention of it in the English literature.

Miramistin | C26H47ClN2O - PubChem

“Conventional antiseptics contaminate the environment because they are toxic to microbiota, fish, algae, and plants,” said Professor David Denning from the University of Manchester, who was on the research team. “These are widely available but problematic, whereas Miramistin has no genotoxic effects after it has been broken down.”

Dr. Ali Osmanov says, “Miramistin has been overlooked in the West and may have practical and environmental advantages.”

Widely used antiseptics with chlorinated aromatic structures including triclosan and triclocarban barely degrade and so persist in the environment for long significant periods, even decades. In contrast, Miramistin is 88–93% biodegradable

The study is published in the journal FEMS Microbiology Reviews.

Lead author Dr. Ali Osmanov, awarded a scholarship to study fungal disease at Manchester, examined Miramistin in the lab for his dissertation project.

When in his native country, Ukraine, he discovered extensive clinical use of Miramistin, causing him to consider if it might be useful elsewhere.

He said: “Miramistin has been overlooked in the West and may have practical and environmental advantages.

Today, antiseptics act as a ‘last frontier’ against antibiotic-resistant bacteria and viruses, and also have important role in infection control. Unfortunately, currently used antiseptics have some flaws.

For example, bleach can exacerbate asthma, and many of the older antiseptics are not active against coronaviruses. We hope our paper will stimulate modern studies to evaluate Miramistin’s potential. Considering emerging antimicrobial resistance, the significant potential of miramistin justifies its re-evaluation for use in other geographical areas and conditions.”


The coronavirus family recently gained a new member in SARS-CoV-2 to go along with SARS-CoV and MERS-CoV. Infection with SARS-CoV-2 causes COVID-19 which has rapidly become a pandemic (with at the time of writing millions infected and hundreds of thousands dead) requiring social distancing, leading to global shutdowns, resulting in a recession, and pushing healthcare infrastructures to the breaking point.

This pandemic is demanding an urgent response and we need to rapidly find treatments which can be accomplished by using existing drugs. Thus, drug repurposing for COVID-19 has garnered mainstream attention which did not occur in previous epidemics (1).

Initially the response from China and elsewhere was for scientists to look at compounds tested previously against SARS and MERS almost exclusively (2).

Ritonavir/lopinavir, remdesivir (repurposed from Ebola and FDA emergency approved), chloroquine and hydroxychloroquine (both now FDA emergency approved, see

Supplementary Material) are the most well-known compounds currently in clinical trials. Other drug repurposing efforts have used computational approaches such as docking or biological network mining to identify molecules as candidates for future testing (2,3,4,5,6,7) (Supplementary Material).

To date there have been few large-scale high-throughput repurposing screens of antiviral inhibition described in the literature (8). These data as well as the earlier SARS and MERS data (9,10) could ultimately be useful for machine learning models in order to predict new molecules from a much wider array of sources and select compounds to test in vitro and in vivo. However, there are only a small number of compounds to date (~100) with reported reliable in vitro data.

Bibliometric Analysis Leads to Quaternary Ammonium Compounds
An exhaustive bibliometric analysis of drug repurposing over the decades conducted by this team recently has described the many drugs that have been tested for other indications (11).

This analysis highlighted chloroquine as one of the most repurposed approved drugs which has been tested against hundreds of diseases (11).

Not surprisingly, chloroquine has also been identified by several groups (in China, South Korea and the USA, (4,5,6,7) to have micromolar activity against SARS-CoV-2 in vitro and along with the derivative hydroxychloroquine has even entered multiple clinical trials (Supplementary Material).

The results have not suggested good efficacy as yet (12) from the limited clinical trial reports. This could be due to a number of reasons such as the metabolism and disposition of these drugs and the therapeutic window. We have now used the same text mining approach to focus solely on drugs that have been used in the treatment of coronaviruses (Supplementary Material, Table S1).

This analysis identified ammonium chloride, which is commonly used as a treatment option for severe cases of metabolicalkalosis, as a drug of interest. Ammonium chloride is a quaternary ammonium compound that is known to also have antiviral activity (13,14) against coronavirus (Supplementary Material) and has a mechanism of action such as raising the endocytic and lysosomal pH, which it shares with chloroquine (15).

Review of the text-mined literature also indicated a high-frequency of quaternary ammonium disinfectants as treatments for many viruses (Supplementary Material) (16,17), including coronaviruses: these act by deactivating the protective lipid coating that enveloped viruses like SARS-CoV-2 rely on.

Quaternary ammonium compounds are widely recommended to kill viruses and there are over 350 products on EPA’s List N: Disinfectants for use against SARS-CoV-2 (Supplementary Material. The disinfectant concentrations and contact times (associated with multiple viruses) for many of the disinfecting chemicals on the EPA list have been reported and > 140 can deactivate the virus in just a few minutes (18).

Cetylpyridinium Chloride and Miramistin
This information led us on a larger search for quaternary ammonium compounds with activity against coronaviruses and possible identification of chemicals that have already been tested in the clinic and could be used as a potential treatment for COVID-19 (Table S2).

One of the disinfectants that has been shown to be destructive to viruses (Supplementary Material) and widely used in personal care products is cetylpyridinium chloride (Table 1) (19,20). This compound is found predominantly in mouthwashes and is listed by the FDA as Generally Regarded as Safe (GRAS) such that it is also being used as an antimicrobial agent for meat and poultry products (up to 1%).

Cetylpyridinium chloride has been used in multiple clinical trials (21), including as a treatment against respiratory infections (21) validating its use as an antiviral.

Cetylpyridinium likely promotes virus inactivation by destroying the capsid as well as through its lysosomotropic action, which, as discussed above, is common for quaternary ammonium compounds.

This raises the question as to whether some of the drugs identified with antiviral activity against SARS-CoV-2 in vitro behave similarly, namely they may destroy the virus capsid as well as accumulating in the lysosome or endosomes and ultimately blocking viral entry.

Additional published studies have suggested that this effect can be attenuated by the use of Cathepsin-L inhibitors (22). Another potential treatment candidate is miramistin (Table 1), a drug belonging to the group of cationic antiseptics, which is also a quaternary ammonium compound reported to have a wide array of biological activities including antiviral against HIV (23).

Miramistin is approved as broad-spectrum anti-infective agent in Russia (24), but it does not appear to have been adopted in the rest of the world. There are numerous FDA approved drugs that have a quaternary nitrogen, and it is possible these could also have a similar broad antiseptic effect.

Table 1 Quaternary ammonium compounds with known coronavirus activity

MoleculeAntiviral activityMechanismFDA approvedUses
Ammonium ChlorideMurine coronavirus, hepatitis C,LysosomotropicYesVarious uses including metabolic acidosis.
Cetylpyridinium chlorideInfluenza, hepatitis B, poliovirus 1Targets capsid and is lysosomotropicYes, GRASAntiseptic, mouthwash, cough lozenges, personal care products, cleaning agents etc.
MiramistinHIV, influenza, herpes, SARSImmunostimulating, targets capsid and is lysosomotropicNo, but is approved in RussiaAntiseptic

The current COVID-19 pandemic is sweeping the globe at an unprecedented rate fanned by our global connectivity. To date it has spurred drug discovery activity (albeit considerably impacted by research laboratory shutdowns) and much interest in drug repurposing in the hope of delivering effective drugs to the patient faster.

The success of this approach will take time to validate as we await clinical trial data from all of the earliest compounds in the clinic. We hypothesized that text mining of the available published literature in PubMed would enable us to identify compounds faster that have been tested against other coronaviruses, but which were not currently being evaluated clinically.

Our studies guided by this approach suggest that while many drugs have been tested, the lysosomotropic agent ammonium chloride and quaternary ammonium compounds such as cetylpyridinium chloride and miramistin may produce the desired antiviral effect but have not as yet been tested against SARS-CoV-2 in vitro or in clinical trials.

We have briefly described this data mining process that identified these classes of compounds of interest and provide our analysis for others to expand up on (Supplementary Material, Table S1).

Limitations of the text mining approach are that at the time of writing there had only been reports of approximately 450 molecules associated with other coronaviruses and many of these could likely be discounted due to no reported antiviral activity, toxicity and perhaps most important, the lack of FDA approved status.

References

  1. Gates B. Responding to Covid-19 – a once-in-a-century pandemic? N Engl J Med. 2020;382:1677–9.CAS Article Google Scholar 
  2. Ekins S, Mottin M, Ramos PRPS, Sousa BKP, Neves BJ, Foil DH, Zorn KM, Braga RC, Coffee M, Southan C, Puhl AC, Andrade CH. Déjà vu: Stimulating Open Drug Discovery for SARS-CoV-2. Drug Discov Today. 2020; Apr 19:S1359-6446(20)30145-8. https://doi.org/10.1016/j.drudis.2020.03.019.
  3. Stebbing J, Phelan A, Griffin I, Tucker C, Oechsle O, Smith D, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400–2.CAS Article Google Scholar 
  4. Jeon S, Ko M, Lee J, Choi I, Byun SY, Park S, Shum D, Kim S. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Available from: https://www.biorxiv.org/content/10.1101/2020.03.20.999730v1.
  5. Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y, Zhang B, Li X, Zhang L, Peng C, Duan Y, Yu J, Wang L, Yang K, liu F, Jiang R, Yang X, You T, Liu X, Yang X, Bai F, Liu H, Liu X, Guddat LW, Xu W, Xiao G, Qin C, Shi Z, Jiang HY, Rao Z, yang H. Structure of Mpro from 1 COVID-19 virus and discovery of its inhibitors. Available from: https://www.biorxiv.org/content/10.1101/2020.02.26.964882v2.
  6. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16.CAS Article Google Scholar 
  7. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71.CAS Article Google Scholar 
  8. Riva L, Yuan S, Yin X, Martin-Sancho L, Matsunaga N, Burgstaller-Muehlbacher S, Pache L, De Jesus PP, Hull MV, Chang M, Chan JF-W, Cao J, Poon VK-M, Herbert K, Nguyen T-T, Pu Y, Nguyen C, Rubanov A, Martinez-Sobrido L, Liu W-C, Miorin L, White KM, Johnson JR, Benner C, Sun R, Schultz PG, Su A, Garcia-Sastre A, Chatterjee AK, Yuen K-Y, Chanda SK. A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals. bioRxiv. 2020:2020.2004.2016.044016.
  9. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875–84.Article Google Scholar 
  10. Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014;58(8):4885–93.Article Google Scholar 
  11. Baker NC, Ekins S, Williams AJ, Tropsha A. A bibliometric review of drug repurposing. Drug Discov Today. 2018;23(3):661–72.CAS Article Google Scholar 
  12. Borba MGS, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, Brito M, Mourao MPG, Brito-Sousa JD, Baia-da-Silva D, Guerra MVF, Hajjar LA, Pinto RC, Balieiro AAS, Pacheco AGF, Santos JDO, Jr., Naveca FG, Xavier MS, Siqueira AM, Schwarzbold A, Croda J, Nogueira ML, Romero GAS, Bassat Q, Fontes CJ, Albuquerque BC, Daniel-Ribeiro CT, Monteiro WM, Lacerda MVG, CloroCovid T. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(4):e208857.Article Google Scholar 
  13. Mizzen L, Hilton A, Cheley S, Anderson R. Attenuation of murine coronavirus infection by ammonium chloride. Virology. 1985;142(2):378–88.CAS Article Google Scholar 
  14. Hoffmann MM, Kleine-Weber H, Kruger N, Muller M, Drosten C, Pohlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor 2 ACE2 and the cellular protease TMPRSS2 for entry into target cells. Available from: https://www.biorxiv.org/content/10.1101/2020.01.31.929042v1.full.pdf.
  15. Ashfaq UA, Javed T, Rehman S, Nawaz Z, Riazuddin S. Lysosomotropic agents as HCV entry inhibitors. Virol J. 2011;8:163.CAS Article Google Scholar 
  16. Rabenau HF, Kampf G, Cinatl J, Doerr HW. Efficacy of various disinfectants against SARS coronavirus. J Hosp Infect. 2005;61(2):107–11.CAS Article Google Scholar 
  17. Dellanno C, Vega Q, Boesenberg D. The antiviral action of common household disinfectants and antiseptics against murine hepatitis virus, a potential surrogate for SARS coronavirus. Am J Infect Control. 2009;37(8):649–52.Article Google Scholar 
  18. Anon. Disinfectant Concentrations and Contact Times for EPA’s List of Products Effective against Novel Coronavirus SARS-CoV-2, the Cause of COVID-19. 2020 1 April. Available from: https://www.ecri.org/components/HDJournal/Pages/Disinfectant-Concentrations-for-EPA-list-N-COVID-19.aspx?tab=2.
  19. Zhu DM, Evans RK. Molecular mechanism and thermodynamics study of plasmid DNA and cationic surfactants interactions. Langmuir. 2006;22(8):3735–43.CAS Article Google Scholar 
  20. Fromm-Dornieden C, Rembe JD, Schafer N, Bohm J, Stuermer EK. Cetylpyridinium chloride and miramistin as antiseptic substances in chronic wound management – prospects and limitations. J Med Microbiol. 2015;64(Pt 4):407–14.CAS Article Google Scholar 
  21. Mukherjee PK, Esper F, Buchheit K, Arters K, Adkins I, Ghannoum MA, et al. Randomized, double-blind, placebo-controlled clinical trial to assess the safety and effectiveness of a novel dual-action oral topical formulation against upper respiratory infections. BMC Infect Dis. 2017;17(1):74.Article Google Scholar 
  22. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci U S A. 2005;102(33):11876–81.CAS Article Google Scholar 
  23. Krivorutchenko Iu L. KrivosheinIuS, Marennikova SS, Stepanova LG, Nosik DN, Kalnina LB, Rud’ko AP. [study of the anti-HIV activity of miramistin]. Vopr Virusol. 1994;39(6):267–9.CAS PubMed Google Scholar 
  24. Agafonov AP, Skarnovich MO, Petrishchenko VA, Shishkina LN, Sergeev AN, Svistov VV, et al. In vitro study of antiviral activity of Myramistin against subtypes H3N2 and H5N1 of influenza virus. Antibiot Khimioter. 2005;50(12):9–11.CAS PubMed Google Scholar 

More information: Ali Osmanov et al. The antiseptic Miramistin: a review of its comparative in vitro and clinical activity, FEMS Microbiology Reviews (2020). DOI: 10.1093/femsre/fuaa012

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.