A novel ciprofloxacin analogue enables daptomycin-mediated killing of resistant Staphylococcus aureus by increasing septum formation

Abstract

Quinolone antibiotics such as ciprofloxacin inhibit DNA gyrase, leading to DNA double-strand breaks that result in rapid bacterial killing and induction of the mutagenic SOS DNA repair response. By contrast, the ciprofloxacin analogue IMP-1700 inhibits ciprofloxacin-induced SOS, suggesting a novel mechanism of action. Here, we provide evidence that IMP-1700 targets the quinolone binding domain of DNA gyrase but triggers a significantly higher frequency of division septa in S. aureus compared with other DNA gyrase targeting antibiotics, including ciprofloxacin. In keeping with this finding, the lipopeptide antibiotic daptomycin, which targets the division septum, bound more strongly to IMP-1700-treated cells relative to S. aureus exposed to other DNA gyrase inhibitors, leading to increased bacterial killing. This finding extended to a panel of paired daptomycin susceptible and resistant clinical isolates. We conclude that the ciprofloxacin analogue IMP-1700 has distinct effects on the cell envelope of S. aureus, despite appearing to share the same target as the parent drug, which result in the resensitisation of daptomycin resistant bacteria to the lipopeptide antibiotic.