ArticleProceedings of the National Academy of Sciences of the United States of America2013
Identification of the molecular attributes required for aminoglycoside activity against Leishmania.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Pathogenic Significance of Trypanosomatids: Progress in Drug Resistance, Control Strategies, and Artificial Intelligence.Interdisciplinary perspectives on infectious diseases · 2026Review
- Mechanism of read-through enhancement by aminoglycosides and mefloquine.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- In Silico Exploration of the Trypanothione Reductase (TryR) ofInternational journal of molecular sciences · 2023Article
- Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis,Frontiers in chemistry · 2021Article
- The Novel Serine/Threonine Protein Kinase LmjF.22.0810 fromBiomolecules · 2019Article
- Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei.Antimicrobial agents and chemotherapy · 2019Article
- Strategies against Nonsense: Oxadiazoles as Translational Readthrough-Inducing Drugs (TRIDs).International journal of molecular sciences · 2019Review
- Influence of Na+ and Mg2+ ions on RNA structures studied with molecular dynamics simulations.Nucleic acids research · 2018Article
- Exploring eukaryoticMedChemComm · 2018Article
- Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities.Chemical Society reviews · 2018Review
- A structural basis for the antibiotic resistance conferred by an N1-methylation of A1408 in 16S rRNA.Nucleic acids research · 2017Article
- Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin.Nature communications · 2017Article
- Reaction Catalyzed by GenK, a Cobalamin-Dependent Radical S-Adenosyl-l-methionine Methyltransferase in the Biosynthetic Pathway of Gentamicin, Proceeds with Retention of Configuration.Journal of the American Chemical Society · 2017Article
- A Synthetic Strategy for Conjugation of Paromomycin to Cell-Penetrating Tat(48-60) for Delivery and Visualization into Leishmania Parasites.International journal of peptides · 2017Article
- Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations.ACS medicinal chemistry letters · 2016Article
- Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics.Nucleic acids research · 2015Article
- Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis.Chemical reviews · 2014Review
- When Proteins Start to Make Sense: Fine-tuning Aminoglycosides for PTC Suppression Therapy.MedChemComm · 2014Article
- New trends in aminoglycosides use.MedChemComm · 2014Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects millions of people worldwide. Aminoglycosides are mostly known as highly potent, broad-spectrum antibiotics that exert their antibacterial activity by selectively targeting the decoding A site of the bacterial ribosome, leading to aberrant protein synthesis. Recently, some aminoglycosides have been clinically approved and are currently used worldwide for the treatment of leishmaniasis; however the molecular details by which aminoglycosides induce their deleterious effect on Leishmaina is still rather obscure. Based on high conservation of the decoding site among all kingdoms, it is assumed that the putative binding site of these agents in Leishmania is the ribosomal A site. However, although recent X-ray crystal structures of the bacterial ribosome in complex with aminoglycosides shed light on the mechanism of aminoglycosides action as antibiotics, no such data are presently available regarding their binding site in Leishmania. We present crystal structures of two different aminoglycoside molecules bound to a model of the Leishmania ribosomal A site: Geneticin (G418), a potent aminoglycoside for the treatment of leishmaniasis at a 2.65-Å resolution, and Apramycin, shown to be a strong binder to the leishmanial ribosome lacking an antileishmanial activity at 1.4-Å resolution. The structural data, coupled with in vitro inhibition measurements on two strains of Leishmania, provide insight as to the source of the difference in inhibitory activity of different Aminoglycosides. The combined structural and physiological data sets the ground for rational design of new, and more specific, aminoglycoside derivatives as potential therapeutic agents against leishmaniasis.
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