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Meetings & Workshops

Talks

  1. JUN

    26

    Wednesday

    CBMS Lecture Series

    "Ribosome-targeting antibiotics overcoming antimicrobial resistance"

    Presented by Yuri Polikanov, University of Chicago

    1:30 pm, Videoconference / Virtual Event

    Wednesday, June 26, 2024, 1:30 pm

    Hosted by: Vivian Stojanoff

    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.

  2. JUL

    24

    Wednesday

    CBMS Lecture Series

    "TBA"

    Presented by Thomas van de Kamp

    1:30 pm, Videoconference / Virtual Event

    Wednesday, July 24, 2024, 1:30 pm

    Hosted by: Vivian Stojanoff