Variants of the lantibiotic MU1140 and other lantibiotics with improved pharmacological properties and structural features
Inventors
Hillman, Jeffrey D. • SMITH, JAMES LEIF • Wilson-Stanford, Shawanda R.
Assignees
Texas A&M University System • Oragenics Inc • Texas A&M University
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Publication Number
US-9963488-B2
Publication Date
2018-05-08
Expiration Date
Abstract
The invention provides improvements of lantibiotics useful for reducing the numbers of microbes or the reproduction of microbes in or on subjects or objects. One embodiment of the invention provides variants of antibiotics wherein the amino acid at position (1) is changed to Ile or Gly, the amino acid at position (4) is changed to an Ala, the amino acid at position (4) is removed, the amino acid at position (5) is changed to an Ala, or wherein, as in the case of MU1140, the amino acid at position (13) is Arg, the Arg at position (13) is substituted with Asp, or combinations of two or more these changes or a pharmaceutically acceptable salt thereof.
Core Innovation
The patent describes improved variants of the lantibiotic mutacin MU1140, including MU1140-like lantibiotics. The variants are defined by substitutions and/or deletions at defined numbered positions within a Formula I, with specified residue options at positions 1, 4, 5, 8, 13, 14, and 22, and the patent links these structural changes to functional behavior and binding relevant to the MU1140 framework.
The problem addressed is to provide MU1140 lantibiotic variants with improved bioactivity, including activity against Gram-positive bacteria and, with appropriate formulations, also Gram-negative bacteria. Selected MU1140 variants show increased bioactivity in bioassays, and the patent includes MIC data for purified variants.
Embodiments further describe antimicrobial compositions and uses for the variants, including preservative use, food-related uses, and treatments of surfaces, medical-device coatings, textiles, and biofilm or biofouling conditions. The document also describes formulation concepts such as antimicrobial compositions and membrane disrupting agent contexts for Gram-negative susceptibility, with structural and functional rationale in terms of hinge flexibility, ring assembly, and lipid II binding associated with MU1140.
Claims Coverage
The provided independent claims cover three main invention categories: specific variant MU1140 lantibiotics defined by a Formula I residue pattern and salts, purified polynucleotides defined by SEQ ID NOs 19-26, and a narrower single Formula I variant MU1140 lantibiotic definition, with dependent refinements into an antimicrobial composition and a reduction method. Overall, the claim set defines multiple inventive residue-feature combinations and associated compositions and uses for controlling bacterial reproduction or numbers.
Formula I variant MU1140 lantibiotic residue pattern
A variant MU1140 lantibiotic comprising Formula I, wherein X at position 1, X at position 4, X at position 5, X at position 13, X at position 8, X at position 14, and X at position 22 are defined by specified options, including multiple alternative sub-combinations listed as (i) through (xiv), and further including a pharmaceutically acceptable salt thereof.
Purified polynucleotide with SEQ ID NOs 19-26
A purified polynucleotide comprising SEQ ID NOs: 19-26 or combinations thereof.
Fixed Formula I variant MU1140 lantibiotic residues with salt
A variant MU1140 lantibiotic comprising Formula I, wherein the X at position 1 is Ile, the X at position 4 is Trp, the X at position 5 is Dha, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, the X at position 22 is —CH=CH— or —CH2—CH2—, and the variant comprises a pharmaceutically acceptable salt thereof.
Across the independent claims, protection is directed to defined MU1140 variant lantibiotics specified by Formula I residue substitutions at multiple numbered positions, to purified polynucleotides comprising SEQ ID NOs 19-26, and to a specific fixed Formula I variant defined by fixed residues with selected variability and included pharmaceutically acceptable salts.
Stated Advantages
Increased bioactivity for selected MU1140 variants as reported in zone-of-inhibition assays.
Ability to reduce bacterial reproduction or reduce numbers of bacteria in or on biofilm or biofouling conditions.
Documented Applications
Antimicrobial composition uses including preservatives and foods, including application to surface and medical-device coatings and textiles.
Methods for reducing bacterial reproduction or reducing numbers of bacteria in subject(s), object(s), or within a composition.
Biofilm or biofouling treatment by contacting the variant MU1140 lantibiotic with the biofilm or biofouling condition for a period effective to reduce reproduction of bacteria or reduce numbers of bacteria in or on the biofilm or biofouling condition.
Use of variants in preservative formulations in a physiological solution at a pH between 3 and 8.
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