Abstract

Antibiotics with new mechanisms of action are urgently required to combat the growing health
threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic
antibiotics, based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a
lead compound that was active in the nanomolar range against gram-negative Pseudomonas sp.,
but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical
and genetic studies showed the peptidomimetics had a non-membrane-lytic mechanism of action
and identified a homologue of the ß-barrel protein LptD (Imp/OstA), which functions in outer
membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial
activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a
serious health problem, so this family of antibiotics may have important therapeutic applications.