Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance
A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by <i>nsp12-nsp7-nsp8</i>) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally appr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-05-01
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| Series: | Microorganisms |
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| Online Access: | https://www.mdpi.com/2076-2607/9/5/1094 |
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| author | Alfredo Mari Tim Roloff Madlen Stange Kirstine K. Søgaard Erblin Asllanaj Gerardo Tauriello Leila Tamara Alexander Michael Schweitzer Karoline Leuzinger Alexander Gensch Aurélien E. Martinez Julia Bielicki Hans Pargger Martin Siegemund Christian H. Nickel Roland Bingisser Michael Osthoff Stefano Bassetti Parham Sendi Manuel Battegay Catia Marzolini Helena M. B. Seth-Smith Torsten Schwede Hans H. Hirsch Adrian Egli |
| author_facet | Alfredo Mari Tim Roloff Madlen Stange Kirstine K. Søgaard Erblin Asllanaj Gerardo Tauriello Leila Tamara Alexander Michael Schweitzer Karoline Leuzinger Alexander Gensch Aurélien E. Martinez Julia Bielicki Hans Pargger Martin Siegemund Christian H. Nickel Roland Bingisser Michael Osthoff Stefano Bassetti Parham Sendi Manuel Battegay Catia Marzolini Helena M. B. Seth-Smith Torsten Schwede Hans H. Hirsch Adrian Egli |
| author_sort | Alfredo Mari |
| collection | DOAJ |
| description | A variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by <i>nsp12-nsp7-nsp8</i>) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting <i>nsp12</i> (Tajima’s D = −2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic. |
| first_indexed | 2024-03-10T11:14:48Z |
| format | Article |
| id | doaj.art-0e9050037aa3400eab49b93fad05b6b2 |
| institution | Directory Open Access Journal |
| issn | 2076-2607 |
| language | English |
| last_indexed | 2024-03-10T11:14:48Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Microorganisms |
| spelling | doaj.art-0e9050037aa3400eab49b93fad05b6b22023-11-21T20:28:32ZengMDPI AGMicroorganisms2076-26072021-05-0195109410.3390/microorganisms9051094Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug ResistanceAlfredo Mari0Tim Roloff1Madlen Stange2Kirstine K. Søgaard3Erblin Asllanaj4Gerardo Tauriello5Leila Tamara Alexander6Michael Schweitzer7Karoline Leuzinger8Alexander Gensch9Aurélien E. Martinez10Julia Bielicki11Hans Pargger12Martin Siegemund13Christian H. Nickel14Roland Bingisser15Michael Osthoff16Stefano Bassetti17Parham Sendi18Manuel Battegay19Catia Marzolini20Helena M. B. Seth-Smith21Torsten Schwede22Hans H. Hirsch23Adrian Egli24Applied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandSIB Swiss Institute of Bioinformatics, 4053-4056 Basel, SwitzerlandSIB Swiss Institute of Bioinformatics, 4053-4056 Basel, SwitzerlandSIB Swiss Institute of Bioinformatics, 4053-4056 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandClinical Virology, University Hospital Basel, 4031 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandInfectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, 4031 Basel, SwitzerlandPediatric Infectious Diseases, University of Basel Children’s Hospital, 4056 Basel, SwitzerlandIntensive Care Medicine, University Hospital Basel, 4031 Basel, SwitzerlandIntensive Care Medicine, University Hospital Basel, 4031 Basel, SwitzerlandEmergency Medicine, University Hospital Basel, 4031 Basel, SwitzerlandEmergency Medicine, University Hospital Basel, 4031 Basel, SwitzerlandInternal Medicine, University Hospital Basel, 4031 Basel, SwitzerlandInternal Medicine, University Hospital Basel, 4031 Basel, SwitzerlandInfectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, 4031 Basel, SwitzerlandInfectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, 4031 Basel, SwitzerlandInfectious Diseases and Hospital Epidemiology, University Hospital Basel and University of Basel, 4031 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandSIB Swiss Institute of Bioinformatics, 4053-4056 Basel, SwitzerlandClinical Virology, University Hospital Basel, 4031 Basel, SwitzerlandApplied Microbiology Research, Department of Biomedicine, University of Basel, 4056 Basel, SwitzerlandA variety of antiviral treatments for COVID-19 have been investigated, involving many repurposed drugs. Currently, the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp, encoded by <i>nsp12-nsp7-nsp8</i>) has been targeted by numerous inhibitors, e.g., remdesivir, the only provisionally approved treatment to-date, although the clinical impact of these interventions remains inconclusive. However, the potential emergence of antiviral resistance poses a threat to the efficacy of any successful therapies on a wide scale. Here, we propose a framework to monitor the emergence of antiviral resistance, and as a proof of concept, we address the interaction between RdRp and remdesivir. We show that SARS-CoV-2 RdRp is under purifying selection, that potential escape mutations are rare in circulating lineages, and that those mutations, where present, do not destabilise RdRp. In more than 56,000 viral genomes from 105 countries from the first pandemic wave, we found negative selective pressure affecting <i>nsp12</i> (Tajima’s D = −2.62), with potential antiviral escape mutations in only 0.3% of sequenced genomes. Potential escape mutations included known key residues, such as Nsp12:Val473 and Nsp12:Arg555. Of the potential escape mutations involved globally, in silico structural models found that they were unlikely to be associated with loss of stability in RdRp. No potential escape mutation was found in a local cohort of remdesivir treated patients. Collectively, these findings indicate that RdRp is a suitable drug target, and that remdesivir does not seem to exert high selective pressure. We anticipate our framework to be the starting point of a larger effort for a global monitoring of drug resistance throughout the COVID-19 pandemic.https://www.mdpi.com/2076-2607/9/5/1094diagnosticssurveillanceresistanceevolutionSARS-CoV-2remdesivir |
| spellingShingle | Alfredo Mari Tim Roloff Madlen Stange Kirstine K. Søgaard Erblin Asllanaj Gerardo Tauriello Leila Tamara Alexander Michael Schweitzer Karoline Leuzinger Alexander Gensch Aurélien E. Martinez Julia Bielicki Hans Pargger Martin Siegemund Christian H. Nickel Roland Bingisser Michael Osthoff Stefano Bassetti Parham Sendi Manuel Battegay Catia Marzolini Helena M. B. Seth-Smith Torsten Schwede Hans H. Hirsch Adrian Egli Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance Microorganisms diagnostics surveillance resistance evolution SARS-CoV-2 remdesivir |
| title | Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance |
| title_full | Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance |
| title_fullStr | Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance |
| title_full_unstemmed | Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance |
| title_short | Global Genomic Analysis of SARS-CoV-2 RNA Dependent RNA Polymerase Evolution and Antiviral Drug Resistance |
| title_sort | global genomic analysis of sars cov 2 rna dependent rna polymerase evolution and antiviral drug resistance |
| topic | diagnostics surveillance resistance evolution SARS-CoV-2 remdesivir |
| url | https://www.mdpi.com/2076-2607/9/5/1094 |
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