We report the design and synthesis of macrocyclic peptide-peptoid hybrids (peptomers) as analogs of autoinducing peptide I (AIP-I) from Staphylococcus aureus. Our solid-phase synthetic route includes efficient microwave-assisted reactions and a tandem macrocyclization-cleavage step, and we demonstrate its compatibility with parallel synthesis through the generation of a focused peptomer library. One of the peptomers was capable of stimulating biofilm formation in S. aureus, a phenotype linked to AIP-I receptor (AgrC-I) inhibition.