Cell-penetrating peptide conjugation broadens and strengthens lasso peptide antibiotics
- Lasso peptide antibiotics such as citrocin and microcin J25 inhibit bacterial RNA polymerase but rely on membrane transporters to get in, narrowing their spectrum and inviting resistance.
- Attaching a cell-penetrating peptide to the loop gave conjugates active against all four Gram-negative ESKAPE pathogens tested and more potent than the unmodified parents.
- E. coli uptake studies suggest entry by both transporter-dependent and transporter-independent routes.
💡 Points
Four-for-four Gram-negative ESKAPE coverage suggests transporter-dependent uptake, not the RNAP pharmacophore, was the limiting factor. A cationic CPP is a blunt fix, though: expect serum binding, protease exposure and mammalian membrane liability, so selectivity indices and stability data will decide whether it beats engineering the loop for better transporter recognition. Grafting onto the threaded scaffold looks tractable.