Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A
Year: 2023
Type: article
Abstract: 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.
Source: Nature Communications
Institutions: University of Illinois Chicago, Northeastern University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory
Awards: G102163711, G107546177, G1313983767, G1505794299, Structural basis of Erm-mediated macrolide resistance, G1664757510, G2101401529, G2287611682, G262962599, G2887060908, G3075337988, Molecular mechanisms of action of ribosome-targeting antibiotics., G340565428, G409777406, G4500341707, G498139845, G500928953, G5071743546, G5106849484, Pixel Array Detector for Macromolecular Crystallography, G5397651101, G5607048534, G6183596937, G6848031779, G6918803902, G6922056765, G7368700025, G78868261, G9000031717, G9000051782, Advancing ribosome-targeting antibacterial peptides with a unique mechanism of action, Development and Field Testing of a Novel Reservoir Targeted Antibiotic Against Borrelia burgdorferi, Precise Combination Strategies Targeting Carbapenem-Resistant Klebsiella pneumoniae, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W4384341748