Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides

Abstract

Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, 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 pairstacking 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.

Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM

“…Cryo-EM has been an important tool to investigate the causes of resistance coming from resistant mutant strains, as recently illustrated with the S. aureus erythromycin resistant mutant [ 50 ], or from species which diverge enough in structure like Acinetobacter baumannii [ 51 ], a Gram-negative plant pathogen that remarkably resists antibiotics through multiple mechanisms. In this regard, the development of new drugs and therapies that selectively target pathogens is essential and was the object of several other recent structural studies [ 52 , 53 , 54 ].…”

Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome

“…A complete dataset for each ribosome complex was collected using 0.979 Å wavelength at 100 K from multiple regions of the same crystal using 0.3° oscillations (same as published previously; refs. 32 and 34 ). The raw data were integrated and scaled using the XDS software package ( 35 ).…”

Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

“…Structural information about the mechanism of the ribosome was mostly obtained through X‐ray diffraction from complexes of antibiotics with ribosome single subunits, such as the Thermus thermophilus 30S subunit, 15 Deinococcus radiodurans 50S subunit, 16 and E. coli 50S subunit 17 . With the development of structural biology, scientists have obtained high‐resolution complex structures of 70S subunit with important antibiotics 18–20 . Therefore, the mechanisms of different types of ribosomal antibiotics have been gradually clarified (Figure 2, Table 1).…”