Abstract 2231 Revisiting the Translation Initiation in Bacterial Protein Biosynthesis for Rational Design of Antimicrobial Peptides

Antibiotic resistance has become a major global health concern in recent decades because of the rapid emergence of resistant strains of bacteria, particularly the six ESKAPE pathogens. The accelerated antibiotic-resistance threats have led to unmet needs for the discovery of new compounds distinctly different from present antimicrobials, while antimicrobial peptides as promising alternatives to conventional antibiotics have attracted growing interest recently. Protein biosynthesis is a core metabolic process occurring in all bacteria and a validated target for antibiotic development. Translation initiation as one of the four phases in protein biosynthesis cycle, is the rate-limiting and highly regulated phase. This critical process involves the formation of an initiation complex of the 30S ribosomal subunit with three initiation factors (IF1, IF2, and IF3), initiator tRNA (formyl-methionine-tRNAfMet), mRNA, as well as GTP. Structural and functional studies show that IF1 binds to the 30S subunit and regulates bacterial protein biosynthesis, in which a short α-helix in IF1 is crucial for its ribosomal binding and regulatory functions. Peptides derived from this α-helix in bacterial IF1s were tested and displayed a high ability to inhibit bacterial growth. Since bacterial IF1 is a highly conserved element of the prokaryotic translational apparatus, these results provide a clue for rational design of new antimicrobials. The School of Integrative Biological and Chemical Sciences at UTRGV is grateful for the generous support provided by a Departmental Grant from the Robert A. Welch Foundation (Grant No. BX-0048).