Crystal Structures of a Bioactive 6′-Hydroxy Variant of Sisomicin Bound to the Bacterial and Protozoal Ribosomal Decoding Sites

Jiro Kondo, Mai Koganei, Juan Pablo Maianti, Vu Linh Ly, Stephen Hanessian

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Parasitic infections recognized as neglected tropical diseases are a source of concern for several regions of the world. Aminoglycosides are potent antimicrobial agents that have been extensively studied by biochemical and structural studies in prokaryotes. However, the molecular mechanism of their potential antiprotozoal activity is less well understood. In the present study, we have examined the invitro inhibitory activities of some aminoglycosides with a 6′-hydroxy group on ringI and highlight that one of them, 6′-hydroxysisomicin, exhibits promising activity against a broad range of protozoan parasites. Furthermore, we have conducted X-ray analyses of 6′-hydroxysisomicin bound to the target ribosomal RNA A-sites in order to understand the mechanisms of both its antibacterial and antiprotozoal activities at the molecular level. The unsaturated ringI of 6′-hydroxysisomicin can directly stack on G1491, which is highly conserved in bacterial and protozoal species, through π-π interaction and fits closer to the guanidine base than the typically saturated and hydroxylated ringI of other structurally related aminoglycosides. Consequently, the compound adopts a lower energy conformation within the bacterial and protozoal A-sites and makes pseudo pairs to either A or G at position1408. The A-site-selective binding mode strongly suggests that 6′-hydroxysisomicin is a potential lead for the design of next-generation aminoglycosides targeting a wide variety of infectious diseases.

Original languageEnglish (US)
Pages (from-to)733-739
Number of pages7
JournalChemMedChem
Volume8
Issue number5
DOIs
StatePublished - May 2013
Externally publishedYes

Keywords

  • Aminoglycosides
  • Antibacterial activity
  • Antiprotozoal activity
  • Ribosomal decoding sites
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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