SABRes: in silico detection of drug resistance conferring mutations in subpopulations of SARS-CoV-2 genomes

The emergence of resistance to antiviral drugs increasingly used to treat SARS-CoV-2 infections has been recognised as a significant threat to COVID-19 control. In addition, some SARS-CoV-2 variants of concern appear to be intrinsically resistant to several classes of these antiviral agents. Therefore, there is a critical need for rapid recognition of clinically relevant polymorphisms in SARS-CoV-2 genomes associated with significant reduction of drug activity in virus neutralisation experiments. Here we present SABRes, a bioinformatic tool, which leverages on expanding public datasets of SARS-CoV-2 genomes and allows detection of drug resistance mutations in consensus genomes as well as in viral subpopulations. We have applied SABRes to detect resistance-conferring mutations in 25,197 genomes generated over the course of the SARS-CoV-2 pandemic in Australia and identified 299 genomes containing resistance conferring mutations to the five antiviral therapeutics that retain effectiveness against currently circulating strains of SARS-CoV-2 - Sotrovimab, Bebtelovimab, Remdesivir, Nirmatrelvir and Molnupiravir. These genomes accounted for a 1.18% prevalence of resistant isolates discovered by SABRes, including 80 genomes with resistance conferring mutations found in viral subpopulations. Timely recognition of these mutations within subpopulations is critical as these mutations can provide an advantage under selective pressure and presents an important step forward in our ability to monitor SARS-CoV-2 drug resistance.

Automated summary

The emergence of drug resistance in SARS-CoV-2 is a significant threat to COVID-19 control. Some variants of the virus are naturally resistant to multiple antiviral drugs. In this study, a bioinformatic tool called SABRes was developed to detect drug resistance mutations in SARS-CoV-2 genomes. The tool was applied to analyze 25,197 genomes from the Australian SARS-CoV-2 pandemic and identified 299 genomes with resistance mutations to five antiviral therapeutics. Timely recognition of these mutations, especially within viral subpopulations, is critical for monitoring SARS-CoV-2 drug resistance.