Wednesday, June 26, 2024, 1:30 pm — Videoconference / Virtual Event (see link below)
The ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the Cfr methyltransferase. Another clinically relevant mechanism of resistance to macrolides and PTC-acting lincosamides is N6-dimethylation of the 23S rRNA nucleotide A2058 by the Erm methyltransferases. Recently, we reported design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance, including Cfr and Erm, that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its DFT-calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Finally, by determining two additional X-ray crystal structures of CRM in complex with bacterial ribosomes modified by the rRNA methylases, Cfr and Erm, respectively, we provide the structural bases for engagement of Cfr- and Erm-methylated ribosomes by CRM. Our structures reveal unexpected concessive adjustments by the target that permit CRM to maintain binding where other antibiotics fail.
Hosted by: Vivian Stojanoff
Pre registration required
20153 | INT/EXT | Events Calendar
Not all computers/devices will add this event to your calendar automatically.
A calendar event file named "calendar.ics" will be placed in your downloads location. Depending on how your device/computer is configured, you may have to locate this file and double click on it to add the event to your calendar.
Event dates, times, and locations are subject to change. Event details will not be updated automatically once you add this event to your own calendar. Check the Lab's Events Calendar to ensure that you have the latest event information.