Impairing protein–protein interactions in an essential tRNA modification complex: An innovative antimicrobial strategy against Pseudomonas aeruginosa

3423223; Fondazione Regionale per la RicercaBiomedica of Regione Lombardia,Grant/Award Number: 3423223; Ministerodell'Università e della Ricerca, Grant/AwardNumber: 2020833Y75Protein–protein interactions (PPIs) have been recognized as a promising target forthe development of new drugs, as proved by the growing number of PPI modulatorsreaching clinical trials. In this context, peptides represent a valid alternative to smallmolecules, owing to their unique ability to mimic the target protein structure andinteract with wider surface areas. Among the possible fields of interest, bacterial PPIsrepresent an attractive target to face the urgent necessity to fight antibiotic resis-tance. Growing attention has been paid to the YgjD/YeaZ/YjeE complex responsiblefor the essential t6 A37 tRNA modification in bacteria. We previously identified anα-helix on the surface of Pseudomonas aeruginosa YeaZ, crucial for the YeaZ-YeaZhomodimer formation and the conserved YeaZ-YgjD interactions. Herein, we presentour studies for impairing the PPIs involved in the formation of the YeaZ dimersthrough synthetic peptide derivatives of this helical moiety, both in vitro with purifiedcomponents and on P. aeruginosa cells. Our results proved the possibility of targetingthose PPIs which are usually essential for protein functioning and thus are refractoryto mutational changes and antibiotic resistance development