Antiviral Activity of Approved Antibacterial, Antifungal, Antiprotozoal and Anthelmintic Drugs: Chances for Drug Repurposing for Antiviral Drug Discovery

Figures & data

Table 1 Possible Mechanism for Antiviral Activity of Approved Antibacterial, Antifungal, Antiprotozoal and Anthelmintic Agents

Drug	Suggested Mechanism of Action	Type of Study	Susceptible Virus	References
1. Antibacterial drugs
1.1. Macrolides
Azithromycin	Blocking viral internalization into host cells during the early phase of infection	In vitro	Influenza A virus (H1N1)	[^Citation67]
Clarithromycin	Inhibiting viral fusion with host cell, through reducing expression of isoform A of the Rashomologus (Rho) family (RhoA).	In vitro	Respiratory syncytial virus	[^Citation162]
Erythromycin	Reducing intercellular adhesion molecule 1 (ICAM-1)	In vitro	Rhinovirus	[^Citation86]
	Blocking rhinovirus-induced MUC5AC protein over production and blocking rhinovirus-induced p44/42 MAPK activation	In vitro	Rhinovirus	[^Citation87]
Fidaxomicin	Inhibiting RNA-dependent RNA polymerase	In vitro	Zika virus	[^Citation21]
	Inhibiting RNA-dependent RNA polymerase	In silico	SARS-CoV-2	[^Citation57]
1.2. Quinolones
Moxifloxacin	Acting on viral main protease (Mpro)	In silico	SARS-CoV-2	[^Citation58]
Ofloxacin	Inhibiting large tumour antigen (T Ag) helicase activity	In vitro	Simian virus 40	[^Citation144]
Levofloxacin	Reducing intercellular adhesion molecule 1 (ICAM-1) and the number of acidic endosomes	In vitro	Rhinovirus	[^Citation88]
	Inhibiting large tumour antigen (T Ag) helicase activity	In vitro	BK virus	[^Citation147]
Ciprofloxacin	Decreasing large tumour antigen (T Ag) expression	In vitro	BK virus	[^Citation141]
	Inhibiting large tumour antigen (T Ag) helicase activity	In vitro	Simian virus 40	[^Citation144]
	Acting on viral main protease (Mpro)	In silico	SARS-CoV-2	[^Citation58]
1.3. Tetracyclines
Doxycycline	Interfering with the interactions between the E protein and the host surface receptor (inhibit viral entry).	In silico	Dengue virus	[^Citation27]
	Inhibiting viral serine protease.	In vitro	Dengue virus	[^Citation28]
	Disrupting the interactions between virus RNA and nucleoprotein.	In silico	CCHFV	[^Citation166]
	Interfering with viral cysteine protease and E2 envelope glycoprotein	In silico	CHIKV	[^Citation131]
Lymecycline	Interfering with 3-chymotrypsin-like protease (3CLpro) and helicase (Nsp13)	In silico	SARS-CoV	[^Citation51]
Oxytetracycline	Interfering with 3-chymotrypsin-like protease (3CLpro)	In silico	SARS-CoV	[^Citation51]
Tigecycline	Interfering with papain-like protease (PLpro)	In silico	SARS-CoV	[^Citation51]
Minocycline	Reducing level of apoptosis signal-regulating kinase 1 (ASK1)	In vitro	HIV and SIV	[^Citation100]
1.4. Other antibacterial drugs
Rifampicin	Acting on viral Main Protease (Mpro)	In silico	SARS-CoV-2	[^Citation60]
Cycloserine	Reducing syncytium formation and p24 protein production	In vitro	HIV-1	[^Citation119]
Fusidic acid	Reducing syncytium formation and inhibit reverse transcriptase	In vitro	HIV-1	[^Citation114,Citation116]
Chloramphenicol	Interfering with papain-like protease (PLpro)	In silico	SARS-CoV	[^Citation51]
2. Antifungal drugs
Amphotericin B	Impairing the attachment and internalization of the virus by host cells.	In vitro	Enterovirus 71	[^Citation96]
Posaconazole	Affecting intracellular cholesterol distribution by targeting oxysterol-binding protein	In vitro	Dengue virus	[^Citation39]
Itraconazole	Suppressing viral RNA replication or polyprotein processing	In vitro	Enterovirus 71	[^Citation93]
	Affecting intracellular cholesterol distribution by targeting oxysterol-binding protein	In vitro	Dengue virus	[^Citation39]
Caspofungin	Acting on viral main protease (Mpro)	In silico	SARS-CoV and SARS-CoV-2	[^Citation63]
	Acting on viral nonstructural protein 12	In vitro	SARS-CoV-2	[^Citation64]
3. Antiprotozoal agents
Quinine	Indirectly by inducing host cell defense mechanisms	In vitro	HSV-1	[^Citation16]
	Interfering with terminal glycosylation in Golgi apparatus.	In vitro	HIV-1	[^Citation120,Citation123]
	Inhibiting the post-translational modification of glycoprotein 120 by increasing endosomal pH	In vitro	HIV-1	[^Citation129]
Hydroxychloroquine	Inhibiting the post-translational modification of glycoprotein 120 by increasing endosomal pH	In vitro	HIV-1	[^Citation120]
Atovaquone	Acting on viral main protease (Mpro)	In silico	SARS-CoV-2	[^Citation66]
4. Antihelminthic drugs
Mebendazole	Acting on viral main protease (Mpro)	In silico	SARS-CoV-2	[^Citation66]

Abbreviations: SARS-CoV, severe acute respiratory syndrome coronavirus; CCHFV, Crimean-Congo hemorrhagic fever virus; CHIKV, chikungunya virus; HIV, human immunodeficiency virus; SIV, simian immunodeficiency virus.

Figure 1 Suggested stages of viral infection at which approved antimicrobial agents exert their antiviral effect.

Cameron DW, Kakeya H, Seki M, et al. Efficacy of combination therapy with oseltamivir phosphate and azithromycin for influenza: a multicenter, open-label, randomized study. PLoS One. 2014;9(3):e91293. doi:10.1371/journal.pone.0091293

 PubMed Web of Science ®Google Scholar

Bawage SS, Tiwari PM, Pillai S, Dennis VA, Singh SR. Antibiotic minocycline prevents respiratory syncytial virus infection. Viruses. 2019;11(8):739. doi:10.3390/v11080739

 PubMed Web of Science ®Google Scholar

Inoue D, Kubo H, Sasaki T, et al. Erythromycin attenuates MUC5AC synthesis and secretion in cultured human tracheal cells infected with RV14. Respirology. 2008;13(2):215–220. doi:10.1111/j.1440-1843.2007.01227.x

 PubMed Web of Science ®Google Scholar

Yamaya M, Nishimura H, Hatachi Y, et al. Levofloxacin inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells. Antimicrob Agents Chemother. 2012;56(8):4052–4061. doi:10.1128/AAC.00259-12

 PubMed Web of Science ®Google Scholar

Yuan J, Yu J, Huang Y, et al. Antibiotic fidaxomicin is an RdRp inhibitor as a potential new therapeutic agent against Zika virus. BMC Med. 2020;18(1):204. doi:10.1186/s12916-020-01663-1

 PubMed Web of Science ®Google Scholar

Marciniec K, Beberok A, Pęcak P, Boryczka S, Wrześniok D. Ciprofloxacin and moxifloxacin could interact with SARS-CoV-2 protease: preliminary in silico analysis. Pharmacol Rep. 2020;72(6):1553–1561. doi:10.1007/s43440-020-00169-0

 PubMed Web of Science ®Google Scholar

Yu D, Sun S, Li Y, et al. Treatment with arbidol and moxifloxacin in ordinary and severe adult patients infected with COVID-19. medRxiv. 2020. doi:10.1101/2020.05.30.20117598

 Google Scholar

Toptas T, Kaygusuz-Atagunduz I, Kani HT, Adiguzel C, Firatli-Tuglular T. Levofloxacin for the treatment of severe refractory BK virus-associated hemorrhagic cystitis in hematopoietic stem cell transplantation recipients: a report of three cases. Oncol Lett. 2014;8(4):1775–1777. doi:10.3892/ol.2014.2381

 PubMed Web of Science ®Google Scholar

Acornley JE, Bessell CJ, Bynoe ML, Godtfredsen WO, Knoyle JM. Antiviral activity of sodium fusidate and related compounds. Br J Pharmacol Chemother. 1967;31(2):210–220. doi:10.1111/j.1476-5381.1967.tb01992.x

 PubMed Web of Science ®Google Scholar

Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother. 2009;53(5):1840–1849. doi:10.1128/AAC.01614-08

 PubMed Web of Science ®Google Scholar

Pasternak J, Rajtar B, Stec A, Polz-Dacewicz M. Antiviral activity of ciprofloxacin on BK virus in an in vitro culture – pilot study. J Pre Clin Clin Res. 2017;11(2):116–119. doi:10.26444/jpccr/78587

 Google Scholar

Rothan HA, Mohamed Z, Paydar M, Rahman NA, Yusof R. Inhibitory effect of doxycycline against dengue virus replication in vitro. Arch Virol. 2013;159(4):711–718. doi:10.1007/s00705-013-1880-7

 PubMed Web of Science ®Google Scholar

Khan IA, Siddiqui S, Rehmani S, Kazmi SU, Ali SH. Fluoroquinolones inhibit HCV by targeting its helicase. Antivir Ther. 2011;17(3):467–476. doi:10.3851/IMP1937

 PubMed Web of Science ®Google Scholar

Kvistgaard AS, Pallesen LT, Arias CF, et al. Inhibitory effects of human and bovine milk constituents on rotavirus infections. J Dairy Sci. 2004;87(12):4088–4096. doi:10.3168/jds.S0022-0302(04)73551-1

 PubMed Web of Science ®Google Scholar

Irani DN, Prow NA. Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis. J Neuropathol Exp Neurol. 2007;66(6):533–544. doi:10.1097/01.jnen.0000263867.46070.e2

 PubMed Web of Science ®Google Scholar

Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949. doi:10.1016/j.ijantimicag.2020.105949

 PubMed Web of Science ®Google Scholar

Zink MC, Uhrlaub J, DeWitt J, et al. Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA. 2005;293(16):2003–2011. doi:10.1001/jama.293.16.2003

 PubMed Web of Science ®Google Scholar

Ke -Y-Y, Peng -T-T, Yeh T-K, et al. Artificial intelligence approach fighting COVID-19 with repurposing drugs. Biomed J. 2020;43:355–362. doi:10.21203/rs.3.rs-22546/v1

 PubMed Web of Science ®Google Scholar

Tsai WP, Nara PL, Kung HF, Oroszlan S. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retroviruses. 1990;6(4):481–489. doi:10.1089/aid.1990.6.481

 PubMed Web of Science ®Google Scholar

Famularo G, Simone CD, Tzantzoglou S, Trinchieri V, Moretti S, Tonietti G. In vivo and in vitro efficacy of fusidic acid in HIV infection. Ann N Y Acad Sci. 1993;685(1 Immunomodulat):341–343. doi:10.1111/j.1749-6632.1993.tb35885.x

 PubMed Web of Science ®Google Scholar

Bourinbaiar AS, Lee-Huang S. Comparative in vitro study of contraceptive agents with anti-HIV activity: gramicidin, nonoxynol-9, and gossypol. Contraception. 1994;49(2):131–137. doi:10.1016/0010-7824(94)90088-4

 PubMed Web of Science ®Google Scholar

Kim C, Kang H, Kim D-E, et al. Antiviral activity of micafungin against enterovirus 71. Virol J. 2016;13(1):1–9. doi:10.1186/s12985-016-0557-8

 PubMed Web of Science ®Google Scholar

Balasubramanian A, Teramoto T, Kulkarni AA, Bhattacharjee AK, Padmanabhan R. Antiviral activities of selected antimalarials against dengue virus type 2 and Zika virus. Antiviral Res. 2017;137:141–150. doi:10.1016/j.antiviral.2016.11.015

 PubMed Web of Science ®Google Scholar

Lee J-S, Choi H-J, Song J-H, Ko H-J, Yoon K, Seong J-M. Antiviral activity of itraconazole against echovirus 30 infection in vitro. Osong Public Health Res Perspect. 2017;8(5):318–324. doi:10.24171/j.phrp.2017.8.5.05

 PubMedGoogle Scholar

Wang M, Ye F, Su J, et al. Caspofungin and LTX-315 inhibit SARS-CoV-2 replication by targeting the nsp12 polymerase. PREPRINT. 2020. doi:10.21203/rs.3.rs-19872/v1

 Google Scholar

Olaleye OA, Kaur M, Onyenaka C, Adebusuyi T. Discovery of clioquinol and analogues as novel inhibitors of severe acute respiratory syndrome coronavirus 2 infection, ACE2 and ACE2 - spike protein interaction in vitro. bioRxiv. 2020. doi:10.1101/2020.08.14.250480

 Google Scholar

Baroni A, Paoletti I, Ruocco E, et al. Antiviral effects of quinine sulfate on HSV-1 HaCat cells infected: analysis of the molecular mechanisms involved. J Dermatol Sci. 2007;47(3):253–255. doi:10.1016/j.jdermsci.2007.05.009

 PubMed Web of Science ®Google Scholar

Boelaert JR, Sperber K, Piette J. Chloroquine exerts an additive in vitro anti-HIV type 1 effect when associated with didanosine and hydroxyurea. AIDS Res Hum Retroviruses. 1999;15(14):1241–1247. doi:10.1089/088922299310133

 PubMed Web of Science ®Google Scholar

Neely M, Kalyesubula I, Bagenda D, Myers C, Olness K. Effect of chloroquine on human immunodeficiency virus (HIV) vertical transmission. Afr Health Sci. 2003;3(2):61–67.

 PubMedGoogle Scholar

Oguariri RM, Adelsberger JW, Baseler MW, Imamichi T. Evaluation of the effect of pyrimethamine, an antimalarial drug, on HIV-1 replication. Virus Res. 2010;153(2):269–276. doi:10.1016/j.virusres.2010.08.018

 PubMed Web of Science ®Google Scholar

Tran DH, Sugamata R, Hirose T, et al. Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process. J Antibiot (Tokyo). 2019;72(10):759–768. doi:10.1038/s41429-019-0204-x

 PubMed Web of Science ®Google Scholar