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YURY POLIKANOV Biological Sciences University of Illinois Chicago WEDNESDAY, June 26, 13:30 (EDT) "Ribosome-targeting antibiotics overcoming antimicrobial resistance" Register in advance for this meeting: https://bnl.zoomgov.com/meeting/register/vJIsc-ispjIoHHZ4eAioVLG4Awm7mM-56rw Time conversion Link: https://www.worldtimebuddy.com/<https://urldefense.com/v3/__https:/gcc02.safelinks.protection.outlook.com/?url=https*3A*2F*2Fwww.worldtimebuddy.com*2F&data=05*7C01*7Cgenoa.blankenship*40pnnl.gov*7C67ffe754733240e42d3e08da641ba4bc*7Cd6faa5f90ae240338c0130048a38deeb*7C0*7C0*7C637932367171794987*7CUnknown*7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0*3D*7C3000*7C*7C*7C&sdata=aSe2IUSomjge9ZW6zXdQ81fPzxpg8eawtRkoiOEJdXM*3D&reserved=0__;JSUlJSUlJSUlJSUlJSUlJSUlJSU!!P4SdNyxKAPE!Fd5kIAbibocFpkUaEbpqZZGm8tw-xiqb5oC4sfOklv6Kbbf-T3RvUobMSLrzyXNbfNVT9vMxJGuY1RsSqbc6MjpIABre1Q$> Abstract: 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. ================= Vivian Stojanoff, PhD Education, Training, Outreach User Program p 1(631) 344 8375 e lifescie...@bnl.gov<mailto:lifescie...@bnl.gov> w https://www.bnl.gov/ps/lifesciences/<https://www.bnl.gov/ps/lsbr/> Address: Center for Biomolecular Structure National Synchrotron Light Source II Building 745 Brookhaven National Laboratory Upton NY 11973 ######################################################################## To unsubscribe from the CCP4BB list, click the following link: https://www.jiscmail.ac.uk/cgi-bin/WA-JISC.exe?SUBED1=CCP4BB&A=1 This message was issued to members of www.jiscmail.ac.uk/CCP4BB, a mailing list hosted by www.jiscmail.ac.uk, terms & conditions are available at https://www.jiscmail.ac.uk/policyandsecurity/
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