COVID-19 – New therapeutic oportunities produced by bacteria in soil?

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Some researchers from the Rockefeller University (USA) have recently published a research program that encompasses not only the prophylaxis, but also the treatment of COVID-19.

SARS-CoV-2 (the infectious agent of COVID-19) is an RNA virus that contains, besides other non-structural proteins, an enzyme, RNA-dependent RNA-polymerase, which represents a main target for inhibiting the viral replication. The Rockefeller Research Program describes innovative approaches for developing potential novel inhibitors of the RNA-dependent RNA-polymerase.

Image source: https://www.nature.com/articles/d41573-020-00016-0

At this moment, a lot of compounds, whose therapeutic effect is related to a mechanism of inhibition of this enzyme, are being studied worldwide. In the therapeutic protocol of the SARS-CoV-2 published by the Ministry of Health of Romania on 23rd March 2020, the use of Remdevisir (an antiviral drug) was approved for treating the critically ill patients. Remdesivir is a nucleotide analog inhibitor of the RNA-dependent RNA-polymerase that competes with ATP (its natural counterpart) and when it is incorporated in the newly formed RNA molecule, it arrests the RNA synthesis after the addition of 3 more nucleotides. Through this mechanism, it inhibits the multiplication of the virus (Gordon et al., 2020).

The originality of this program resides in the source of the possible novel inhibitors of the enzyme. Chemist Sean Brady has been involved in the discovery of novel antibiotics made by bacteria in soil, using methods that do not require isolation nor the culture of these microorganisms. In one of his studies, there was observed an efficient activity of some compounds against certain bacterial strains that show resistance to different antibiotics. These compounds are codified by a family of gene clusters identified in the soil metagenomes. Moreover, his studies tackled the inhibition mechanism the RNA-dependent RNA-polymerase of the resistant strains of Mycobacterium tuberculosis (the causative agent of tuberculosis).

Only a part of the bacterial diversity is regularly cultivated in the laboratory and furthermore, only several chemical products encoded by cultured bacteria are detected during experiments. As a consequence, the vast majority of bacterial natural products remain hidden in the global microbiome. With the aim of having access to these hidden compounds, a research team that includes Sean Brady developed a platform for revealing the culture-independent bacterial natural products. In order to create this platform, they extracted the DNA from the environmental samples and, afterwards, performed sequencing, bioinformatic analysis and heterologous expression of the captured biosynthetic gene clusters. (Hover et al., 2018)

Brady has extended his studies to the human microbiome, having shown that there are multiple novel nucleosides, which are likely to be involved in the inhibition of RNA and DNA polymerases produced by different microorganisms. Having said that, he might have discovered a large source for identifying a specific inhibitor of the SARS-CoV-2 RNA polymerase which nobody had taken advantage of for this purpose yet. The potential novel inhibitors can be tested in screening assays that are being developed by Charlie Rice, professor at Rockefeller University.

The whole description of the Rockefeller University Research Program on COVID-19/SARS-COV-2 can be found at https://www.rockefeller.edu/coronavirus/research-program-covid-19-sars-cov-2/

Bibliography

1.https://www.rockefeller.edu/coronavirus/research-program-covid-19-sars-cov-2/

2.Gordon, C. J., Tchesnokov, E. P., Feng, J. Y., Porter, D. P., & Gotte, M. (2020). The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus, Journal of Biological Chemistry, jbc-AC120.

3.Hover, B. M., Kim, S. H., Katz, M., Charlop-Powers, Z., Owen, J. G., Ternei, M. A., … & Perlin, D. S. (2018). Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens, Nature microbiology,3(4), 415-422.

4.Peek, J., Lilic, M., Montiel, D., Milshteyn, A., Woodworth, I., Biggins, J. B., … & Saito, K. (2018). Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism, Nature communications,9(1), 1-15.

 

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