Peptide Inhibitors of Bacterial Protein Synthesis with Broad Spectrum and SbmA-Independent Bactericidal Activity against Clinical Pathogens

Proline-rich antimicrobial
peptides (PrAMPs) are promising lead
compounds for developing new antimicrobials; however, their narrow
spectrum of action is limiting. PrAMPs kill bacteria binding to their
ribosomes and inhibiting protein synthesis. In this study, 133 derivatives
of the PrAMP Bac7(1–16) were synthesized to identify the crucial
residues for ribosome inactivation and antimicrobial activity. Then,
five new Bac7(1–16) derivatives were conceived and characterized
by antibacterial and membrane permeabilization assays, X-ray crystallography,
and molecular dynamics simulations. Some derivatives displayed broad
spectrum activity, encompassing Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas
aeruginosa, and Staphylococcus aureus. Two peptides out of five acquired a weak membrane-perturbing activity
while maintaining the ability to inhibit protein synthesis. These
derivatives became independent of the SbmA transporter, commonly used
by native PrAMPs, suggesting that they obtained a novel route to enter
bacterial cells. PrAMP-derived compounds could become new-generation
antimicrobials to combat antibiotic-resistant pathogens.