Repositioning Adequate Antibiotics to Treat/Cure the Coronavirus Disease 2019 (COVID-19): Current Treatments and Future Directions

Abstract

Aims: Rational use of antibiotics against the betacoronavirus SARS-CoV-2 responsible for the COVID-19 pandemic. Objective: Repositioning and repurposing adequate antibiotics to cure the Coronavirus Disease 2019 (COVID-19). Background: It is widely accepted that viral infections such as the SARS-CoV-2 cannot be cured by antibiotics, whereas bacterial infections can. It is because the SARS-CoV-2 virus has no protein synthesis machinery (usually targeted by antibiotics) to produce from its RNA genome, the viral proteins and enzymes essential for its replication and/or for the assembly of viral particles. However, the antibiotics must be capable of inhibiting the ribosomes of the protein synthesis machinery of the SARS-CoV-2-infected human host cells, in order to prevent them from synthesizing new proteins that they do not need, but are needed for the virus to spread. Unfortunately, the only antibiotic capable of selectively inhibiting the human 80S ribosomes, namely cycloheximide, was found to be a poisonous drug for the mammals. Therefore, the only possibility is to search for the antibiotics that are capable of inhibiting both bacterial and eukaryal ribosomes, in order to prevent at the same time the ribosomes of the infected human host cells from synthesizing the proteins and enzymes for the SARS-CoV-2 virus, and those of the eventual opportunistic pathogenic bacteria from developing pneumonia. Methods: First, we have used a molecular modeling study involving the tools of the semi-empirical quantum mechanics PM3 method to study the interaction between the cation Zn++ and all the molecules considered as zinc transporters in this report. By this approach, the niche in which Zn++ is located was determined. Such an interaction serves as a shuttle and allows zinc cation to invade endocellular structures in the SARS-CoV-2-infected human host cells. Second, we have measured the poly (U)-dependent poly (Phe) synthesis activity of human 80S ribosomes in the presence of increasing concentrations of four antibiotics of the class of the macrolides, namely erythromycin, azithromycin, clarithromycin and telithromycin. This experiment led us to determine for each macrolide, the half-inhibitory concentration (IC50) that is the concentration of antibiotic corresponding to 50% inhibition of the activity of the human 80S ribosomes. Finally, we have analyzed previously published data from the group of Nierhaus (Berlin) on the competition between the incoming aminoacyl-tRNA and the antibiotic tetracycline for the binding to the ribosomal A-site on the E. coli 70S or rabbit liver 80S ribosomes. This led to the conclusion by the authors that tetracycline most likely binds to corresponding sites in 70S and 80S ribosomes with comparable affinity. Results: We propose to reposition the macrolides (azithromycin or erythromycin or others) and tetracyclines for the treatment of COVID-19 patients, on account of the following data gathered in this report. First, these antibiotics are already currently successfully used in medicine in humans and animals. Second, the binding sites of these antibiotics at the upper part of the protein exit tunnel (for the macrolides) and the ribosomal A-site (for tetracyclines) are universally conserved features of the ribosomes in all kingdoms of life. So, these classes of antibiotics are expected to bind to all kinds of ribosomes, the 70S as well as the 80S type, with comparable affinity. Therefore, they are capable of preventing at the same time the ribosomes of the infected human host cells from synthesizing the proteins and enzymes for the SARS-CoV-2 virus, and those of the eventual opportunistic pathogenic bacteria from developing pneumonia. Third, the efficacy assessment of these antibiotics in clinical application consisted of comparing their affinity constants of binding to the human ribosomes with their blood concentration. For example, in the case of azithromycin, the amount of antibiotic administered to COVID-19 patients was 100 μg/ml of circulating blood, which is 43 times superior to the half-inhibitory concentration (IC50 or KIa of 2.3 μg/ml), the concentration of azithromycin corresponding to 50% inhibition of the activity of the human 80S ribosomes. Fourth, zinc cations were previously shown to be a strong antiviral agent, while all the macrolides and tetracyclines that we propose for repurposing or repositioning to cure the COVID-19 are shown in the present report to form Zn++-antibiotic complex and behave as efficient zinc transporters into the SARS-CoV-2-infected host cells. Conclusion: The macrolides (azithromycin or erythromycin or others) and tetracyclines selected for repositioning and repurposing to cure COVID-19 are candidates as specific and effective therapeutic drugs available for the coronavirus disease. We propose to combat the current COVID-19 pandemic with azithromycin or erythromycin (or equivalent) alone or in combination with tetracycline (or equivalent) in the presence of Zn++(SO4--). Taking into account the fact that azithromycin had been shown to be effective in treating viral infections such as papillomaviruses in humans and dogs, we conclude that the statement “no antibiotic for viral infections !” is not relevant for all the clinically approved classes of antibiotics, because selective antibiotics such as the universal antibiotics described in the present report are capable of exhibiting antiviral activities through specific interactions with the human 80S ribosomes of infected host cells. As a conclusion, even though the clinical and experimental data presented here do not suggest virucidal activity of azithromycin-zinc or tetracycline-zinc complexes, they do indicate that when administered simultaneously at the onset of first signs of COVID-19, the most common symptoms being fatigue, fever, dry cough, headache, sore throat, muscle pain or shortness of breath, azithromycin (or tetracycline) and zinc cations are capable of inhibiting ribosomal activity of SARS-CoV-2-infected human cells. This results in blocking protein and enzyme synthesis vital for viral RNA replication and for assembly of viral particles. Early treatment allows both reductions of viremia as well as stabilizing symptoms. The major advantage of this therapeutic strategy is avoiding prolonged clinical COVID-19 disease with contingent worsening of illness and subsequent need for intensive care. Prolonged COVID-19 illness is the major downfall of the present pandemic, returning to normal being long, difficult, and sometimes impossible.