key: cord-0009071-4d6d97qd
authors: Colson, Philippe; Raoult, Didier
title: Fighting viruses with antibiotics: an overlooked path
date: 2016-08-05
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2016.07.004
sha: b76f4a4bd2af0739fd5ac82b0783f0c117a14322
doc_id: 9071
cord_uid: 4d6d97qd

nan

explored by different biologists and researchers. Hence, the crossover of knowledge and transversality of approaches have been considerably hampered. Even now, with the advent of metagenomics, the microbiota and the virome are usually studied separately and by different teams. For instance, among publications retrieved from the ISI Web of Science using virus or bacteria independently as keywords, only ca. 3-4% are still found when using both terms concurrently.

Three recent articles in 2016 have described that compounds of bacterial origin could inhibit the replication of viruses in vitro [15] [16] [17] ( Table 1) . Wang et al and Zhou et al observed that teicoplanin, a semisynthetic glycopeptide used in the clinic for its activity against Grampositive bacteria, could inhibit Ebola envelope pseudotyped viruses [15, 16] . Teicoplanin is a complex of fermentation products originating from Actinoplanes teichomyceticus, an Actinobacteria member, and exerts its bactericidal effect through inhibition of bacterial cell wall biosynthesis. In their work, Wang et al used pseudotyped Ebola viruses containing a luciferase reporter gene to screen 1280 U.S. Food and Drug Administration (FDA)-approved compounds [15] . They detected that teicoplanin significantly inhibited Vero cell infection by pseudotyped Ebola viruses. Wang et al noted that teicoplanin had already been reported as active against other enveloped viruses [15] . They further observed that this drug was inactive against three picornaviruses, which are non-enveloped viruses, and that it did not inhibit the pseudotyped Ebola virus when tested after viral adsorption to the cell surface. Taken together, these data suggested that teicoplanin blocks the viral entry step. In a second study, Zhou et al tested 1600 FDA-approved drugs and also observed that teicoplanin inhibited HEK293T cell infection by pseudotyped Ebola viruses [16] . This team further found evidence that the teicoplanin target was located on the host cells and was cathepsin L, which performs glycoprotein proteolysis required for membrane fusion during the entry step of Ebola viruses and SARS-CoV. Finally, other teicoplanin and glycopeptide antibiotics, including dalbavancin, oritavancin and telavancin, but not vancomycin, were found to inhibit the entry of Ebola virus, SARS-CoV and MERS-CoV transcription-and replicationcompetent virus-like particles. In a third study, Varghese et al identified that ivermectin and abamectin were active on Chikungunya virus [17] . Both drugs derive from avermectin, which is produced by the bacterium Streptomyces avermitilis and whose discovery was awarded the Nobel Prize in Medicine in 2015 [30] . Ivermectin and abamectin are macrocyclic lactones with a wellknown broad activity spectrum against parasites. Ivermectin is widely used in human and veterinary medicine, whereas abamectin is used on agricultural crops. Varghese et al used a fully automated chikungunya-replicon cell line-based assay to screen a panel of 2933 compounds, which included clinically approved drugs as well as drugs in clinical trials [17] . They found that ivermectin and abamectin inhibited chikungunya virus replication in a dose-dependent manner and decreased the synthesis of genomic RNA, antigenomic RNA and proteins from this virus. In addition, these drugs were also efficient against Semliki Forest virus and Sindbis virus, two other alphaviruses, and on yellow fever virus, a flavivirus, suggesting broad antiviral activity. These three articles are the most recent examples of reports on the antiviral activity of drugs of bacterial origin. Previously, teicoplanin had already been reported as active against HIV, hepatitis C virus, flaviviruses, coronaviruses, respiratory syncytial virus and influenza virus [15] . In addition, ivermectin had been previously shown to inhibit the NS3 helicase of three flaviviruses, namely yellow fever virus, dengue virus and West Nile virus [27] ( Table 1) . Among other examples of drugs of bacterial origin that are active against viruses, previous works showed the activity of valinomycin, a cyclododecadepsipeptide produced by Streptomyces, against the SARS-CoV [31] , and of a bacteriocin produced by Enterococcus faecium against herpes simplex virus [32] . These findings make biological sense. Viruses are currently considered to be the most abundant biological entities on Earth and are estimated to outnumber bacteria and eukaryotes by 1-2 log10, respectively, and viral diversity appears to be tremendous and still largely untapped [33] . Moreover, recent technological advances that include high-throughput sequencing, metagenomics and culturomics have emphasised the concurrent presence in environmental samples, as well as in humans, of viruses, bacteria, archaea and eukaryotes [34] [35] [36] [37] [38] . This indicates that bacteria may not only compete and fight among each other, but also with multiple viruses. Among viruses there are well-known bacteria killers, bacteriophages, which have a major impact on environmental bacterial communities [39] and have been proposed for treating bacterial infections in humans [40] . Conversely, during the past decade, CRISPR have been discovered in bacteria as an amazing mechanism of adaptive immunity against invading viruses, demonstrating that the war is bilateral [41] . Therefore, it can be hypothesised that bacteria could have developed, concurrently with antibiotics, antivirals. Nonetheless, whilst the fact that microbes interact and fight among each other has been in the forefront for decades in bacteriology, their capability to threaten viral replication has been widely overlooked [9] .

The studies by Wang et al [15] , Zhou et al [16] and Varghese et al [17] are only the first steps towards a possible use of antibiotics and antiparasitic drugs derived from bacteria as antivirals, which may represent another example of the benefits of drug repurposing [42, 43] . Their results have to be confirmed, and it has to be determined whether concentrations within the therapeutic range can be achieved to target viruses. Nonetheless, these studies highlight that the potential antiviral activity of antimicrobials may be untapped. Another lesson from these articles regards the strategy chosen to discover drugs with an antiviral effect. Indeed, no hypothesis, prediction or modelling has been made. In contrast, the strategy was straightforward and consisted of massive high-throughput screening of hundreds or thousands of available drugs, regardless of their known activity spectrum and target or their approved indication. This is a different approach than specifically targeting stages of the virus replication cycle through blocking proteins involved in their progress [44] . In addition, aside from the great interest in approved drugs for the potential treatment of viral infections for which we currently lack antivirals, we usually have, as is the case here for teicoplanin and ivermectin, considerable experience with their use in humans, which could accelerate their access to the clinic.

In summary, these recent findings open wide a new field in the fight against viral infections. They highlight the fact that research in bacteriology and virology should not be tightly compartmentalised, and they show that, as has been done for antibiotics and in various other fields [4, 45, 46] , mimicking the living is probably a valuable strategy in improving and expanding our antiviral armamentarium.

Funding: None.

Competing interests: None declared. Ethical approval: Not required.

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study

Emerging infectious diseases: threats to human health and global stability

Coronaviruses-drug discovery and therapeutic options

Infectious disease. Combating emerging viral threats

Tackling latency as a barrier to an HIV cure: what next?

Towards an HBV cure: state-of-the-art and unresolved questions-report of the ANRS Workshop on HBV cure

Antiviral therapy: old and current issues

HIV reservoirs: what, where and how to target them

Looking back in 2009 at the dawning of antiviral therapy now 50 years ago: an historical perspective

80th anniversary of the discovery of penicillin: an appreciation of Sir Alexander Fleming

A brief history of the antibiotic era: lessons learned and challenges for the future

The concept of virus

The development of the virus concept as reflected in corpora of studies on individual pathogens. 1. Beginnings at the turn of the century

Mimivirus inaugurated in the 21st century: the beginning of a reclassification of viruses

Teicoplanin inhibits Ebola pseudovirus infection in cell culture

Glycopeptide antibiotics potently inhibit cathepsin L in the late endosome/lysosome and block the entry of Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus (SARS-CoV)

Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses

An analogue of the antibiotic teicoplanin prevents Flavivirus entry in vitro

Inhibition of feline (FIPV) and human (SARS) coronavirus by semisynthetic derivatives of glycopeptide antibiotics

A few atoms make the difference: synthetic, CD, NMR and computational studies on antiviral and antibacterial activities of glycopeptide antibiotic aglycon derivatives

Semisynthetic teicoplanin derivatives as new influenza virus binding inhibitors: synthesis and antiviral studies

Synthesis of isoindole and benzoisoindole derivatives of teicoplanin pseudoaglycon with remarkable antibacterial and antiviral activities

Polycyclic peptide and glycopeptide antibiotics and their derivatives as inhibitors of HIV entry

Antiretroviral activity of semisynthetic derivatives of glycopeptide antibiotics

Teicoplanin therapy leading to a significant decrease in viral load in a patient with chronic hepatitis C

Inhibition of hepatitis C virus replication by semi-synthetic derivatives of glycopeptide antibiotics

Ivermectin is a potent inhibitor of Flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug

Ivermectin inhibits porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages

Effects of ivermectin on the susceptibility of Culicoides sonorensis (Diptera: Ceratopogonidae) to bluetongue and epizootic hemorrhagic disease viruses

Nobel Prize goes to antiparasitic drug discoverers

Novel potent hepatitis C virus NS3 serine protease inhibitors derived from proline-based macrocycles

Characterisation of an antiviral pediocin-like bacteriocin produced by Enterococcus faecium

Marine viruses-major players in the global ecosystem

Viral and microbial community dynamics in four aquatic environments

Expanding the role of the virome: commensalism in the gut

Bacteria-phage interactions in natural environments

The rebirth of culture in microbiology through the example of culturomics to study human gut microbiota

Repertoire of human gut microbes

Viral influence on aquatic bacterial communities

Exploiting gut bacteriophages for human health

An updated evolutionary classification of CRISPR-Cas systems

Drug repurposing programmes get lift off

Second act: drug repurposing gets a boost as academic researchers join the search for novel uses of existing drugs

Strategies in the design of antiviral drugs

Drug repurposing in chemical genomics: can we learn from the past to improve the future?

Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection

Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Fédération de Bactériologie-Hygiène-Virologie

UM63 CNRS 7278 IRD 198 INSERM U1095