Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A

Chen, Chih-Wei; Leimer, Nadja; Syroegin, Egor A.; Dunand, Clémence; Bulman, Zackery P.; Lewis, Kim; Polikanov, Yury S.; Svetlov, Maxim S.

doi:10.1038/s41467-023-39653-5

Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A

Journal Article · Fri Jul 14 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-39653-5· OSTI ID:2423650

Chen, Chih-Wei ^[1]; ^[2]; Syroegin, Egor A. ^[1]; Dunand, Clémence ^[1]; ^[1]; Lewis, Kim ^[2]; ^[1]; ^[1]

University of Illinois, Chicago, IL (United States)
Northeastern University, Boston, MA (United States)

The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423650

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Antibiotics
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Science & Technology
X-ray crystallography

Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A

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