J Antibiot (Tokyo)

. 2019 Oct;72(10):759-768. doi: 10.1038/s41429-019-0204-x. Epub 2019 Jul 12.

Azithromycin, a 15-membered Macrolide Antibiotic, Inhibits Influenza A(H1N1)pdm09 Virus Infection by Interfering With Virus Internalization Process

Dat Huu Tran ^1 2, Ryuichi Sugamata ^1 2 3, Tomoyasu Hirose ⁴, Shoichi Suzuki ^1 2 3, Yoshihiko Noguchi ⁴, Akihiro Sugawara ^4 5, Fuyu Ito ², Tomoko Yamamoto ², Shoji Kawachi ^2 3, Kiyoko S Akagawa ⁴, Satoshi Ōmura ⁴, Toshiaki Sunazuka ⁴, Naoki Ito ⁶, Masakazu Mimaki ⁶, Kazuo Suzuki ^7 8 9Affiliations expand

• PMID: 31300721
• DOI: 10.1038/s41429-019-0204-x

Abstract

The pandemic influenza 2009 (A(H1N1)pdm09) virus currently causes seasonal and annual epidemic outbreaks. The widespread use of anti-influenza drugs such as neuraminidase and matrix protein 2 (M2) channel inhibitors has resulted in the emergence of drug-resistant influenza viruses. In this study, we aimed to determine the anti-influenza A(H1N1)pdm09 virus activity of azithromycin, a re-positioned macrolide antibiotic with potential as a new anti-influenza candidate, and to elucidate its underlying mechanisms of action. We performed in vitro and in vivo studies to address this. Our in vitro approaches indicated that progeny virus replication was remarkably inhibited by treating viruses with azithromycin before infection; however, azithromycin administration after infection did not affect this process. We next investigated the steps inhibited by azithromycin during virus invasion. Azithromycin did not affect attachment of viruses onto the cell surface, but blocked internalization into host cells during the early phase of infection. We further demonstrated that azithromycin targeted newly budded progeny virus from the host cells and inactivated their endocytic activity. This unique inhibitory mechanism has not been observed for other anti-influenza drugs, indicating the potential activity of azithromycin before and after influenza virus infection. Considering these in vitro observations, we administered azithromycin intranasally to mice infected with A(H1N1)pdm09 virus. Single intranasal azithromycin treatment successfully reduced viral load in the lungs and relieved hypothermia, which was induced by infection. Our findings indicate the possibility that azithromycin could be an effective macrolide for the treatment of human influenza.

Int J Antimicrob Agents

. 2020 May 13;106020. doi: 10.1016/j.ijantimicag.2020.106020. Online ahead of print.

Synergistic Antiviral Effect of Hydroxychloroquine and Azithromycin in Combination Against SARS-CoV-2: What Molecular Dynamics Studies of Virus-Host Interactions Reveal

Jacques Fantini ¹, Henri Chahinian ², Nouara Yahi ²Affiliations expand

• PMID: 32405156
• PMCID: PMC7219429
• DOI: 10.1016/j.ijantimicag.2020.106020

Free PMC article

Abstract

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.

Keywords: Azithromycin; Chloroquine; Coronavirus; Ganglioside; Pandemic; SARS-CoV-2.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Aging (Albany NY)

. 2020 Mar 30;12(8):6511-6517. doi: 10.18632/aging.103001. Epub 2020 Mar 30.

COVID-19 and Chronological Aging: Senolytics and Other Anti-Aging Drugs for the Treatment or Prevention of Corona Virus Infection?

Camillo Sargiacomo ¹, Federica Sotgia ¹, Michael P Lisanti ¹Affiliations expand

• PMID: 32229706
• PMCID: PMC7202514
• DOI: 10.18632/aging.103001

Free PMC article

Abstract

COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is ACE-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.

Keywords: Azithromycin; COVID-19; Doxycycline; Hydroxy-chloroquine; Quercetin; Rapamycin; aging; antibiotic; corona virus; drug repurposing; prevention; senescence; senolytic drug therapy; viral replication.

Conflict of interest statement

CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare.

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