Unveiling Translation Mechanisms in Microbial Pathogens and Characterization of Antibiotic Action: Insights from Fast-Kinetics and Cryo-EM

Numerous clinically administered antibiotics target microbial ribosomes, impeding protein synthesis. Yet, our understanding of the precise mechanism underlying their action remains limited. My laboratory specializes in elucidating the mechanisms behind antibiotic action by studying protein synthesis in bacteria and eukaryotes. Employing fast-kinetics and Cryo-EM techniques together, we've made significant strides in understanding antibiotic actions. Recent breakthroughs include unveiling the modes of action for potent semisynthetic aminoglycosides like Amikacin (Seely et al, Nat Commun 2023) and Arbekacin (Majumder et al, manuscript), surpassing the effectiveness of traditional counterparts e.g. kanamycin. Additionally, our exploration of Thermorubin, akin to Tetracycline but with a distinct binding site and action mechanism, has expanded our understanding about this less explored antibiotic (Parajuli et al, Nat Commun 2023). Furthermore, we have uncovered the translocation mechanism in the eukaryotic pathogen Giardia intestinalis using cryo-EM (Majumdar et al, Nucleic Acids Res 2023). These findings emphasize the combined potency of quantitative biochemistry and cryo-EM in unraveling drug action mechanisms and characterizing microbial drug targets, contributing to improved drug design for combatting global antibiotic resistance problem.