Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides
[1]
- Univ. of Illinois, Chicago, IL (United States)
- Lomonosov Moscow State Univ., Moscow (Russia)
- Lomonosov Moscow State Univ., Moscow (Russia); Skolkovo Inst. of Science and Technology (Russia)
- NRC Kurchatov Inst., Gatchina (Russia); Peter the Great St. Petersburg Polytechnic Univ. (Russia)
- Interbioscreen, Ltd., Chernogolovka, Russia
- Lomonosov Moscow State Univ., Moscow (Russia); Skolkovo Inst. of Science and Technology (Russia); Russian Academy of Sciences, Moscow (Russia)
Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. As such, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chemical moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-methyl side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Office of Research Infrastructure Programs (ORIP); USDOE Office of Science (SC); Illinois State; Russian Foundation for Basic Research (RFBR); Russian Science Foundation (RSF)
- Grant/Contract Number:
- S10 RR029205; S10 OD021527; AC02-06CH11357; R21-AI137584; 17-00-00366; 18-44-04005
- OSTI ID:
- 1543006
- Journal Information:
- Antimicrobial Agents and Chemotherapy, Vol. 63, Issue 6; ISSN 0066-4804
- Publisher:
- American Society for MicrobiologyCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
Web of Science
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journal | October 2019 |
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