Salmochelin-Antibiotic Conjugates for Targeting Gram-Negative Pathogens

Technology #16939

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A cartoon depiction of the enterobactin transport and processing machinery in E. coli.Structures of enterobactin 1 and the salmochelins 2 (monoglucosylated enterobactin (MGE) and 3 (diglucosylated enterobactin, DGE)
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Inventors
Professor Elizabeth Nolan
Department of Chemistry, MIT
External Link (web.mit.edu)
Tengfei Zhen
Department of Chemistry, MIT
Phroom Chairatana
Department of Chemistry, MIT
Managed By
Jon Gilbert
MIT Technology Licensing Officer
Patent Protection

Enterobactin Conjugates and Uses Thereof

US Patent Pending 2015-0105337
Publications
Targeting virulence: salmochelin modification tunes the antibacterial activity spectrum of β-lactams for pathogen-selective killing of Escherichia coli
Royal Society of Chemistry, May 22, 2015, Vol. 6 4458-4471

Applications

Salmochelin-antibiotic conjugates target pathogenic gram-negative bacteria and can be used for therapeutic treatment in humans and other animals.

Problem Addressed

Antibiotic resistance has long been a cause for concern in the microbiology community. Most conventional methods of countering the development of resistance focus on the creation of new antibiotics that target intracellular processes; however, gram-negative bacteria possess an outer membrane that acts as a barrier to antibiotic entry. Spontaneous mutations in these membranes provide gram-negative bacteria new methods of antibiotic resistance. A novel method for the intracellular delivery of existing antibiotics may provide an additional means of targeting pathogenic gram-negative bacteria that bypasses the outer membrane barrier. 

Technology

This invention involves a modified version of salmochelin, which is expressed in pathogenic gram-negative bacteria and which contributes to their pathogenicity. Salmochelin is a siderophore used by these pathogenic bacteria to scavenge for extracellular iron.  Receptors on the outer membrane bind to salmochelin and facilitate the delivery of iron into the cytosol. In this invention, the salmochelin is linked to antibiotics with polyetheylene glycol linkers. The modified salmochelin binds to receptors on the cell membrane and delivers its conjugated antibody into the bacteria. Modified salmochelin is advantageous to non-native antibiotic models because its mechanism of delivery involves native cell machinery. This allows for enhanced recognition and delivery. Moreover, modified salmochelin can easily be adapted to deliver non-antibiotic entities into pathogens, such as other toxic molecules, or even fluorophores or biotin. 

Related to Technology #16976, Sidophore-Based Immunization Against Gram-Negative Bacteria. 

Advantages

  • Combats the development of antibiotic resistance, which occurs when the outer membrane in gram-negative pathogens undergo spontaneous mutation
  • Specific targeting of pathogenic bacteria compared to commensal bacteria
  • Exploitation of native cell machinery to deliver antibiotics
  • Capability of delivering non-antibiotic constructs into pathogens as well