ArticleJournal of the American Chemical Society2019
Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 34 citations in OpenAlex.
- Article
- Breaking resistance: strategies for novel antibacterial therapeutic interventions.Molecular biology reports · 2026Review
- Enantioselective Total Syntheses of Sannamycins A and B.Journal of the American Chemical Society · 2025Article
- Resolving the intricate binding of neomycin B to multiple binding motifs of a neomycin-sensing riboswitch aptamer by native top-down mass spectrometry and NMR spectroscopy.Nucleic acids research · 2024Article
- In vitro susceptibility of Neisseria gonorrhoeae to netilmicin and etimicin in comparison to gentamicin and other aminoglycosides.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2024Article
- Practical Synthesis from Streptomycin and Regioselective Partial Deprotections of (-)-(1The Journal of organic chemistry · 2024Article
- Mechanistic plasticity in ApmA enables aminoglycoside promiscuity for resistance.Nature chemical biology · 2024Article
- Synthesis of Gentamicins C1, C2, and C2a and Antiribosomal and Antibacterial Activity of Gentamicins B1, C1, C1a, C2, C2a, C2b, and X2.ACS infectious diseases · 2023Article
- Glycan Stability and Flexibility: Thermodynamic and Kinetic Characterization of Nonconventional Hydrogen Bonding in Lewis Antigens.Journal of the American Chemical Society · 2023Article
- Ribosome-targeting antibiotics and resistanceRSC medicinal chemistry · 2023Review
- Synthesis of 4-Tetrahedron · 2023Article
- Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Influence of ring size in conformationally restricted ring I analogs of paromomycin on antiribosomal and antibacterial activity.RSC medicinal chemistry · 2021Article
- Synthesis and Antibacterial Activity of Propylamycin Derivatives Functionalized at the 5''- and Other Positions with a View to Overcoming Resistance Due to Aminoglycoside Modifying Enzymes.ACS infectious diseases · 2021Article
- Poly(α-l-lysine)-based nanomaterials for versatile biomedical applications: Current advances and perspectives.Bioactive materials · 2021Review
- En Route to the Transformation of Glycoscience: A Chemist's Perspective on Internal and External Crossroads in Glycochemistry.Journal of the American Chemical Society · 2021Article
- Potential for the Development of a New Generation of Aminoglycoside Antibiotics.Pharmaceutical chemistry journal · 2021Article
- Article
- Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Structural and biochemical analyses of an aminoglycoside 2'-N-acetyltransferase from Mycolicibacterium smegmatis.Scientific reports · 2020Article
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.
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