Covalent PqsC blockers disarm Pseudomonas aeruginosa instead of killing it
- Pathoblocker compounds originally found in Gram-positive bacteria were screened against Pseudomonas aeruginosa, yielding a beta-lactone that shuts down pyocyanin production.
- Activity-based profiling, proteomics, mass spectrometry and mutagenesis pointed to the quorum-sensing enzyme PqsC, with a catalytic cysteine as the covalent attachment site; a crystal structure confirmed the binding mode.
- A follow-up virtual screen produced a chloroacetamide chemotype with better potency, and treated culture supernatants were less toxic to mammalian cells.
💡 Points Based on the abstract
Beta-lactones are a red flag for stability and off-target acylation, so the chloroacetamide follow-up is the more interesting chemotype: tunable warhead reactivity, easy synthesis. Hitting a catalytic cysteine in PqsC is plausible, but I'd want proteome-wide selectivity data before trusting a pathoblocker label.
Chemical Inhibition of Pyocyanin Biosynthesis Attenuates Virulence of Pseudomonas aeruginosa ↗