Antibacterial treatment using aminoglycosides as catalytically disable bacterial ribosome

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Pharmaceuticals and Biotechnology

The Technology

The emergence of multidrug-resistant pathogens that are resistant to most currently available antibiotics is a significant clinical problem. The development of new antibacterial agents and novel approaches is therefore extremely important. One innovative approach is the development of catalytic antibiotics: the pharmacophore of an existing antibiotic is modified to include a catalytic warhead that disables the target in a catalytic manner. These antibiotics acting in a catalytic manner promote multiple turnovers of a catalytic cycle. The possible benefits include 1) activity at lower dosages and consequently reduced side effects, 2) activity against drug‐resistant bacteria, and 3) reduced potential for generating new resistance. A mode for the catalytic action of a neomycin B derivative on the hydrolysis of the phosphodiester bond between G1491 and A1492 in the decoding site of ribosomal RNA is proposed. The ethylenediamine moiety linked at the 4′‐position of neomycin B serves as the catalytic warhead to cleave the phosphodiester bond through acid–base catalysis The new derivatives showed significant antibacterial activity against wild‐type bacteria and were especially potent against resistant and pathogenic strains including Pseudomonas aeruginosa and methicillin‐resistant Staphylococcus aureus.

Advantages

  • Promote multiple turnovers of a catalytic cycle Biocompatible
  • Activity at lower dosages and consequently reduced side effects
  • Activity against drug‐resistant bacteria
  • Reduced potential for generating new resistance.

Applications and Opportunities

  • New antibacterial agent
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Dr. Ruth Gross
Director of Business Development, Life Sciences