A novel E198K substitution in the PA gene of influenza A virus with reduced susceptibility to baloxavir acid

Baloxavir acid (BXA), the active compound in baloxavir marboxil (BXM), reduces the propagation of influenza A and B viruses by inhibiting the cap-dependent endonuclease activity of the polymerase acidic (PA) subunit. Although BXM has been used to treat influenza virus infections, recently, there has been general concern about the emergence of viruses with low susceptibility to BXA. Here, we identified a novel PA subunit substitution, PA E198K, that reduced susceptibility to BXA. The IC 50 of BXA toward influenza A viruses containing PA E198K increased approximately 2- to 6-fold. These findings help to understand the mechanism by which PA substitutions reduce susceptibility to BXA.