S. aureus SH1000 isolates passaged with zoliflodicin exhibit altered susceptibility to IMP-1700. Staphylococcus aureus SH1000 passaged with Zoliflodicin

Initial work found that the GyrA subunit of S. aureus DNA gyrase was the target of IMP-1700. In silico docking predicted that IMP-1700 has a potential second interaction with the TOPRIM domain of the GyrB subunit of DNA gyrase. Because zoliflodicin targets this domain in GyrB, S. aureus SH1000 isolates were passaged with increasing concentrations of zoliflodicin to generate resistant isolates with increased MICs to the drug. WGS confirmed GyrB substitutions in the TOPRIM domain of these isolates. The isolates also exhibited altered susceptibility to IMP-1700 showing that the GyrB TOPRIM domain is important for the bacteriostatic activity of the compound.