Bacterial Secretion System Combined with Probiotics to Deliver Antisense Therapies

University of Colorado Boulder Background
Antibiotic-resistant bacteria are threatening our ability to treat common infections causing an estimated 20 billion dollars in direct healthcare costs. This health crisis is due to the intersection of rapidly evolving antibiotic-resistant bacteria and the lack of new antibiotics being developed. In particular, bacterial pathogens in urgent need of effective antibiotics include Enterobacteriaceae such as carbapenem-resistant Enterobacteriaceae Escherichia coli and extended spectrum β-lactamase producing Klebsiella pneumoniae which were both recently designated priority one critical class by the World Health Organization. Current antibiotics are limited to small molecules targeting proteins within three main pathways in bacteria: cellular replication, protein biosynthesis, and cell wall biosynthesis. There are 303 essential genes in E. coli with 139 of those existing in non-traditional antibiotic pathways such as metabolism, cell motility and secretion, and those of unknown function. Exploring nontraditional antibiotic targets expands the realm of potential therapeutics and introduces bacteria to new stresses to which they have not developed resistance. Recent research efforts to identify novel small molecules by isolating microorganisms from specific niches (e.g., the discovery of teixobactin from soil microorganism) are promising but involve tedious, time-consuming screening processes. A strategy involving antisense therapeutics enables sequence-specific targeting of RNA, allowing for the design of molecules which target essential genes in non-traditional antibiotic target pathways.
Technology Overview
Researchers at the University of Colorado have developed new classes of antibiotics by targeting non-traditional pathways and genes using sequence-specific peptide nucleic acids (PNAs). PNAs designed to target essential genes in pathways including metabolism, cell signaling, and stress response are capable of killing or inhibiting MDR clinical isolates. Using predictive homology, these PNAs were designed to target varied species of Enterobacteriaceae and were found to demonstrate therapeutic potential against a range of MDR bacteria including carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase (ESBL) Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae and MDR Salmonella enterica. These MDR clinical isolates were found to be resistant to most classes of antibiotics, with genome sequencing revealing as high as sixteen resistance genes, yet PNAs were able to potentiate the activity of traditional antibiotics. This technology enables the use of a bacterial Type III secretion system to overcome limitations of transport typically associated with PNAs to treat an intracellular infection of Salmonella of human epithelial cells.

Stage of Development

Antisense technology
Antibiotics in non-traditional pathways
Rationally designed therapy
Type III secretion systems

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