Tunicamycin related compounds with anti-bacterial activity
Inventors
Assignees
US Department of Agriculture USDA
Publication Number
US-10513533-B2
Publication Date
2019-12-24
Expiration Date
2038-01-16
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Abstract
Tunicamycin related compounds having an acyl chain double bond reduced and/or having an acyl chain double bond and an uracil ring double bond reduced are described as well as methods of making these tunicamycin related compounds. These tunicamycin related compounds are not toxic to eukaryotic cells and can be used to kill Gram-positive bacteria, alone or in combination with other antibiotics. Use of these tunicamycin related compounds to kill Gram-positive bacteria, treat Gram-positive bacterial diseases, and disinfect objects or surfaces are described. In addition, naturally-occurring streptovirudin compounds are not toxic to eukaryotic cells and can be used to kill Gram-positive bacteria, alone or in combination with other antibiotics.
Core Innovation
The invention relates to tunicamycin related compounds that have been chemically modified to reduce one or two double bonds—specifically, an acyl chain double bond and/or a uracil ring double bond. These modifications result in tunicamycin related compounds that possess antibacterial activity against Gram-positive bacteria while exhibiting significantly reduced or no toxicity to eukaryotic cells and animals, including humans.
The problem addressed by this invention arises from the known toxicity of natural tunicamycins to eukaryotic cells, which precludes their use as antibiotics in humans and animals. Although tunicamycins effectively inhibit bacterial cell wall teichoic acid biosynthesis and can restore β-lactam antibiotic efficacy against resistant bacteria such as MRSA, their high toxicity limits therapeutic application. The invention solves this problem by producing new tunicamycin related compounds with reduced eukaryotic toxicity but retained antibacterial efficacy.
Specifically, the invention provides single-reduced tunicamycins (Tun-R1) where the fatty acid acyl chain double bond is reduced, double-reduced tunicamycins (Tun-R2) where both the acyl chain double bond and the uracil ring double bond are reduced, and naturally occurring streptovirudin compounds (Tun-R3) with distinct double bond configurations. These tunicamycin related compounds can be used alone or in combination with β-lactam or other antibiotics to kill Gram-positive bacteria. Methods for the synthesis of these compounds from unmodified tunicamycins via chemical hydrogenation in acidic organic solvents with catalysts are also included.
Claims Coverage
The patent contains one independent claim directed to a tunicamycin related compound of Formula 2, along with independent claims covering related antibacterial compositions, methods of killing Gram-positive bacteria, treating bacterial infections, disinfecting surfaces, and methods of making the tunicamycin related compound.
Tunicamycin related compound with double bond reductions
A tunicamycin related compound comprising Formula 2 characterized by chemical reduction of the fatty acid acyl chain double bond and the uracil ring double bond, resulting in diminished eukaryotic toxicity and retained antibacterial activity.
Antibacterial composition containing tunicamycin related compounds
Compositions comprising at least one tunicamycin related compound of Formula 2, optionally combined with an antibiotic including β-lactam antibiotics (such as penicillins, cephalosporins, monobactams, carbapenems) or non-β-lactam antibiotics.
Methods of killing Gram-positive bacteria and treating infections
Methods of killing Gram-positive bacteria or treating Gram-positive bacterial infections in animals by administering effective amounts of the antibacterial compositions containing tunicamycin related compounds of Formula 2, alone or in combination with β-lactam or other antibiotics.
Methods of disinfecting surfaces or objects
Methods for disinfecting objects or surfaces bearing Gram-positive bacteria by applying effective amounts of tunicamycin related compounds of Formula 2 to kill or inhibit bacterial growth.
Methods of making tunicamycin related compounds
Methods of producing tunicamycin related compounds of Formula 2 by exposing unmodified tunicamycin to a sufficient acidified organic solvent, catalyst (such as palladium on carbon), and hydrogenation agent (such as sodium borohydride), under controlled temperature and time conditions, followed by catalyst removal and purification steps.
The claims collectively cover tunicamycin related compounds chemically reduced at specific double bonds, their use in antibacterial compositions including combinations with β-lactam antibiotics, methods of bacterial kill and infection treatment, disinfection methods, and methods of chemical synthesis resulting in compounds with reduced eukaryotic toxicity and effective antibacterial activity.
Stated Advantages
The tunicamycin related compounds retain potent antibacterial activity against Gram-positive bacteria despite chemical modification.
These compounds exhibit greatly reduced or negligible toxicity to eukaryotic cells including mammalian cell lines and yeast.
The tunicamycin related compounds synergistically enhance the efficacy of β-lactam antibiotics, including overcoming resistance in bacteria such as MRSA.
The compounds enable safer therapeutic use of tunicamycin-like antibiotics in animals and humans due to reduced cytotoxicity.
The disclosed synthesis methods provide a practical chemical route to obtain these less toxic, antibacterial tunicamycin derivatives.
Documented Applications
Killing Gram-positive bacteria in or on animals, including treatment of bacterial infections.
Antibacterial compositions combining tunicamycin related compounds with β-lactam or other antibiotics to enhance antibacterial efficacy.
Disinfecting objects or surfaces contaminated with Gram-positive bacteria to kill or inhibit bacterial growth.
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