Design of novel antibiotics that bind to the ribosomal acyltransfer site

J Am Chem Soc. 2002 Apr 3;124(13):3229-37. doi: 10.1021/ja011695m.


The structure of neamine bound to the A site of the bacterial ribosomal RNA was used in the design of novel aminoglycosides. The design took into account stereo and electronic contributions to interactions between RNA and aminoglycosides, as well as a random search of 273 000 compounds from the Cambridge structural database and the National Cancer Institute 3-D database that would fit in the ribosomal aminoglycoside-binding pocket. A total of seven compounds were designed and subsequently synthesized, with the expectation that they would bind to the A-site RNA. Indeed, all synthetic compounds were found to bind to the target RNA comparably to the parent antibiotic neamine, with dissociation constants in the lower micromolar range. The synthetic compounds were evaluated for antibacterial activity against a set of important pathogenic bacteria. These designer antibiotics showed considerably enhanced antibacterial activities against these pathogens, including organisms that hyperexpressed resistance enzymes to aminoglycosides. Furthermore, analyses of four of the synthetic compounds with two important purified resistance enzymes for aminoglycosides indicated that the compounds were very poor substrates; hence the activity of these synthetic antibiotics does not appear to be compromised by the existing resistance mechanisms, as supported by both in vivo and in vitro experiments. The design principles disclosed herein hold the promise of the generation of a large series of designer antibiotics uncompromised by the existing mechanisms of resistance.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases / metabolism
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / metabolism*
  • Anti-Bacterial Agents / pharmacology
  • Binding Sites
  • Carbohydrate Sequence
  • Drug Design
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Kinetics
  • Models, Chemical
  • Molecular Sequence Data
  • Neomycin / analogs & derivatives*
  • Neomycin / metabolism
  • Neomycin / pharmacology
  • Nucleic Acid Conformation
  • RNA, Ribosomal, 16S / chemistry
  • RNA, Ribosomal, 16S / metabolism*
  • Structure-Activity Relationship


  • Anti-Bacterial Agents
  • RNA, Ribosomal, 16S
  • Acetyltransferases
  • Neomycin