Ebselen analogs hit bacterial polyphosphate kinases to blunt P. aeruginosa virulence
- Ebselen-derived compounds were developed to inhibit both PPK1 and PPK2 from Pseudomonas aeruginosa, disrupting the bacterium's polyphosphate balance.
- Lead analogs lowered intracellular polyphosphate and reproduced the ppk-knockout phenotype: weaker biofilms, reduced motility and less pyoverdine and pyocyanin.
- In a Galleria infection model they enhanced meropenem activity, and the representative compounds showed no detectable toxicity to mammalian cells.
💡 Points Based on the abstract
Ebselen is a classic promiscuous Se–N electrophile that arylselenylates cysteines, so dual PPK1/PPK2 inhibition likely reflects covalent thiol engagement rather than a tuned binding mode. Still open: thiol-reactivity counter-screens (GSH, unrelated Cys enzymes) and a ppk-null strain showing the phenotype and meropenem synergy are on-target. The obvious follow-up is tuning benzisoselenazolone electrophilicity for selectivity.