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Publication Number
US-9024005-B2
Publication Date
2015-05-05
Expiration Date
Abstract
The present invention relates to complexes of transcription factor decoys, their delivery to bacteria and their formulation. In particular, the present invention resides in an antibacterial complex comprising a nucleic acid sequence and one or more delivery moieties selected from quaternary amine compounds; bis-aminoalkanes and unsaturated derivatives thereof, wherein the amino component of the aminoalkane is an amino group forming part of a heterocyclic ring; and an antibacterial peptide.
Core Innovation
The invention relates to antibacterial transcription factor decoy (TFD) nucleic acid complexes. The complexes comprise a double stranded nucleic acid sequence that contains a native cellular binding site for a bacterial transcription factor and has a length of 40 to 100 nucleotides. The nucleic acid self-anneals to form the binding site for the bacterial transcription factor.
The nucleic acid sequence is complexed with at least one delivery moiety to form an antibacterial complex. The delivery moiety is described as having specific formula-based chemical families, including quaternary amine compounds, bis-aminoalkanes and/or unsaturated derivatives forming heterocyclic ring amino groups, and antibacterial peptides.
The disclosure provides a rationale for using transcription factor decoys to sequester transcription factors and thereby prevent virulence and essential gene expression, with a reduced likelihood of resistance. The complexes are described as characterized for complex size and binding stability and are supported by in vitro and in vivo activity, including growth inhibition/killing against MRSA (EMRSA-15/EMRSA-16) and E. coli.
Claims Coverage
The partial content provides coverage for one independent claim (clm-00001). The claim defines two main inventive aspects: a specific nucleic acid transcription-factor binding-site construct with length and self-annealing behavior, and an antibacterial delivery-moiety-complex architecture that carries the construct into bacteria.
Native cellular transcription factor binding site nucleic acid delivery construct
The nucleic acid sequence comprises the sequence of a native cellular binding site for a bacterial transcription factor and is 40 to 100 nucleotides in length and self-anneals to form the binding site for the bacterial transcription factor.
Antibacterial complex with double stranded nucleic acid and delivery moiety
An antibacterial complex comprising a double stranded nucleic acid sequence and at least one delivery moiety.
Self-annealing formation of the bacterial transcription factor binding site
The nucleic acid self-anneals to form the binding site for the bacterial transcription factor.
Delivery-moiety-formula based quaternary/heterocyclic amino composition
The delivery moiety has the formula, as specified in the independent claim (formula content not included in the provided partial text).
Across clm-00001 and its dependent refinements, the inventive core is the antibacterial complex of a double stranded nucleic acid carrying a native bacterial transcription factor binding site of 40–100 nucleotides that self-anneals to form the binding site, combined with a delivery moiety defined by specified formula families; dependent claims further narrow the transcription-factor target to SigB or Fur and optionally to specific SEQ ID NOs.
Stated Advantages
Sequesters transcription factors to prevent virulence and essential gene expression.
Reduced likelihood of resistance.
Shows growth inhibition/killing activity against MRSA (EMRSA-15/EMRSA-16) and E. coli.
Delivery enhancement using antibacterial peptides.
Documented Applications
Therapeutic treatment of bacterial infections using pharmaceutical or medicament compositions containing the antibacterial complexes; possible combination with antibiotics is described.
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