Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 07 2023
14 07 2023
Historique:
received:
31
01
2023
accepted:
22
06
2023
medline:
17
7
2023
pubmed:
15
7
2023
entrez:
14
7
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37452045
doi: 10.1038/s41467-023-39653-5
pii: 10.1038/s41467-023-39653-5
pmc: PMC10349075
doi:
Substances chimiques
Macrolides
0
hygromycin A
3YJY415DDI
Anti-Bacterial Agents
0
Cinnamates
0
Hygromycin B
3XQ2233B0B
Ketolides
0
Protein Synthesis Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4196Subventions
Organisme : NIAID NIH HHS
ID : R21 AI137584
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI152210
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132302
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI173064
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI162961
Pays : United States
Informations de copyright
© 2023. The Author(s).
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