4. Antibiotic inhibition of the ribosome

Protein synthesis is a key target for antibiotic-mediated regulation. In fact, antibiotics have been identified that inhibit almost every step of the translation cycle. Today, all major classes of ribosome-targeting antibiotics have been visualized in complex with a ribosomal particle, which together with a plethora of biochemical studies, have provided not only insight into the mechanism of inhibition of the antibiotic, but also an in-depth understanding of the fundamental process of protein synthesis. However, the prevalence of antibiotic-resistant strains of pathogenic bacteria within the clinical setting is ever-increasing, prompting the need for the development of novel and more potent antibiotics. Following the introduction of the quinolones (ciprofloxacin) and streptogramins (Synercid) into clinical practice the early 1960’s, only three truly new classes of antibiotics have followed in the subsequent ~50 years; the oxazolidinones (linezolid, 2000), lipopeptides (daptomycin, 2003) and more recently the pleuromutilins (retapamulin, 2007). Nevertheless, in the intervening years a number of new semi-synthetic derivatives have been developed based on the original natural parent compound, for example, telithromycin from erythromycin and tigecycline from tetracycline. These second and third generation antibiotics display improved activity against some multi-drug resistant pathogenic strains, while still utilizing the same core scaffold and binding site as the original parent compound and are thus ultimately vulnerable to some level of cross-resistance. The Wilson group is interested in structurally and chemically characterizing the interaction of antibiotics with the ribosome and identifying the functional states of the ribosome that are targeted by different classes of antibiotics. Ultimately, an understanding of the mode of interaction of antibiotics with the ribosome will enables the development of new improved antimicrobial agents that can overcome multi-drug resistant bacteria.