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Identification of the molecular attributes required for aminoglycoside activity against Leishmania.

Shalev M, Kondo J, Kopelyanskiy D, Jaffe CL, Adir N, Baasov T
Proc Natl Acad Sci U S A 110 13333-8 (2013)
Cited: 23 times
EuropePMC logo PMID: 23898171

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.

Articles - 4k31 mentioned but not cited (3)

  1. Atomic resolution snapshot of Leishmania ribosome inhibition by the aminoglycoside paromomycin. Shalev-Benami M, Zhang Y, Rozenberg H, Nobe Y, Taoka M, Matzov D, Zimmerman E, Bashan A, Isobe T, Jaffe CL, Yonath A, Skiniotis G. Nat Commun 8 1589 (2017)
  2. Influence of Na+ and Mg2+ ions on RNA structures studied with molecular dynamics simulations. Fischer NM, Polêto MD, Steuer J, van der Spoel D. Nucleic Acids Res 46 4872-4882 (2018)
  3. Identification of the molecular attributes required for aminoglycoside activity against Leishmania. Shalev M, Kondo J, Kopelyanskiy D, Jaffe CL, Adir N, Baasov T. Proc Natl Acad Sci U S A 110 13333-13338 (2013)


Reviews citing this publication (5)

  1. Recent developments in drug discovery for leishmaniasis and human African trypanosomiasis. Nagle AS, Khare S, Kumar AB, Supek F, Buchynskyy A, Mathison CJ, Chennamaneni NK, Pendem N, Buckner FS, Gelb MH, Molteni V. Chem Rev 114 11305-11347 (2014)
  2. Chemotherapy of leishmaniasis: present challenges. Uliana SRB, Trinconi CT, Coelho AC. Parasitology 145 464-480 (2018)
  3. Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities. Thamban Chandrika N, Garneau-Tsodikova S. Chem Soc Rev 47 1189-1249 (2018)
  4. Strategies against Nonsense: Oxadiazoles as Translational Readthrough-Inducing Drugs (TRIDs). Campofelice A, Lentini L, Di Leonardo A, Melfi R, Tutone M, Pace A, Pibiri I. Int J Mol Sci 20 E3329 (2019)
  5. A Bright Future for Antibiotics? Matzov D, Bashan A, Yonath A. Annu Rev Biochem 86 567-583 (2017)

Articles citing this publication (15)

  1. Enhancement of premature stop codon readthrough in the CFTR gene by Ataluren (PTC124) derivatives. Pibiri I, Lentini L, Melfi R, Gallucci G, Pace A, Spinello A, Barone G, Di Leonardo A. Eur J Med Chem 101 236-244 (2015)
  2. When Proteins Start to Make Sense: Fine-tuning Aminoglycosides for PTC Suppression Therapy. Shalev M, Baasov T. Medchemcomm 5 1092-1105 (2014)
  3. Reaction Catalyzed by GenK, a Cobalamin-Dependent Radical S-Adenosyl-l-methionine Methyltransferase in the Biosynthetic Pathway of Gentamicin, Proceeds with Retention of Configuration. Kim HJ, Liu YN, McCarty RM, Liu HW. J Am Chem Soc 139 16084-16087 (2017)
  4. Design of Novel Aminoglycoside Derivatives with Enhanced Suppression of Diseases-Causing Nonsense Mutations. Sabbavarapu NM, Shavit M, Degani Y, Smolkin B, Belakhov V, Baasov T. ACS Med Chem Lett 7 418-423 (2016)
  5. Structural basis for selective targeting of leishmanial ribosomes: aminoglycoside derivatives as promising therapeutics. Shalev M, Rozenberg H, Smolkin B, Nasereddin A, Kopelyanskiy D, Belakhov V, Schrepfer T, Schacht J, Jaffe CL, Adir N, Baasov T. Nucleic Acids Res 43 8601-8613 (2015)
  6. Importance of the 6'-hydroxy group and its configuration for apramycin activity. Mandhapati AR, Shcherbakov D, Duscha S, Vasella A, Böttger EC, Crich D. ChemMedChem 9 2074-2083 (2014)
  7. A structural basis for the antibiotic resistance conferred by an N1-methylation of A1408 in 16S rRNA. Kanazawa H, Baba F, Koganei M, Kondo J. Nucleic Acids Res 45 12529-12535 (2017)
  8. Chemogenomic Profiling of Antileishmanial Efficacy and Resistance in the Related Kinetoplastid Parasite Trypanosoma brucei. Collett CF, Kitson C, Baker N, Steele-Stallard HB, Santrot MV, Hutchinson S, Horn D, Alsford S. Antimicrob Agents Chemother 63 e00795-19 (2019)
  9. Leishmanicidal, antiproteolytic, and mutagenic evaluation of alkyltriazoles and alkylphosphocholines. Gontijo VS, Espuri PF, Alves RB, de Camargos LF, Santos FV, de Souza Judice WA, Marques MJ, Freitas RP. Eur J Med Chem 101 24-33 (2015)
  10. The Novel Serine/Threonine Protein Kinase LmjF.22.0810 from Leishmania major may be Involved in the Resistance to Drugs such as Paromomycin. Vacas A, Fernández-Rubio C, Algarabel M, Peña-Guerrero J, Larrea E, Rocha Formiga F, García-Sosa AT, Nguewa PA. Biomolecules 9 E723 (2019)
  11. Exploring eukaryotic versus prokaryotic ribosomal RNA recognition with aminoglycoside derivatives. Sabbavarapu NM, Pieńko T, Zalman BH, Trylska J, Baasov T. Medchemcomm 9 503-508 (2018)
  12. A Synthetic Strategy for Conjugation of Paromomycin to Cell-Penetrating Tat(48-60) for Delivery and Visualization into Leishmania Parasites. Defaus S, Gallo M, Abengózar MA, Rivas L, Andreu D. Int J Pept 2017 4213037 (2017)
  13. Structure-Based Design of a Eukaryote-Selective Antiprotozoal Fluorinated Aminoglycoside. Kanazawa H, Saavedra OM, Maianti JP, Young SA, Izquierdo L, Smith TK, Hanessian S, Kondo J. ChemMedChem 13 1541-1548 (2018)
  14. Benzopyrazine-Based Small Molecule Inhibitors As Trypanocidal and Leishmanicidal Agents: Green Synthesis, In Vitro, and In Silico Evaluations. Rock J, Garcia D, Espino O, Shetu SA, Chan-Bacab MJ, Moo-Puc R, Patel NB, Rivera G, Bandyopadhyay D. Front Chem 9 725892 (2021)
  15. In Silico Exploration of the Trypanothione Reductase (TryR) of L. mexicana. Barrera-Téllez FJ, Prieto-Martínez FD, Hernández-Campos A, Martínez-Mayorga K, Castillo-Bocanegra R. Int J Mol Sci 24 16046 (2023)


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