Anti-bacterial stilbene derivatives and methods of use
Inventors
Crawford, Jason • GODDARD, Tyler • PARK, Hyun Bong • Patel, Jaymin
Assignees
Publication Number
US-12286398-B2
Publication Date
2025-04-29
Expiration Date
2040-04-17
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Abstract
Provided herein are novel antibacterial compounds of Formula I. The compounds can be made through enzymatic oxidative dimerization in the presence of a suitable organism and one or more metal salts. Pathogenic bacteria exposed to the compound of Formula I do not develop resistance to these compounds even after prolonged exposure. Also provided herein are methods of treating bacterial infections, and method of killing or disinfecting bacteria.
Core Innovation
The invention provides novel antibacterial compounds of Formula I, which are structurally defined stilbene derivatives. These compounds can be synthesized through enzymatic oxidative dimerization of stilbene-derived monomers, such as tapinarof, in the presence of a suitable organism and one or more metal salts. The methods of preparation include both biological (using transformed organisms expressing, for example, the Plu1886 gene) and chemical dimerization processes, as well as in situ transformation through the action of the microbiome.
The antibacterial compounds described are capable of killing a broad range of pathogenic bacteria, including antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE). Remarkably, these compounds maintain their antibacterial efficacy over extended exposure and do not induce the development of bacterial resistance after prolonged contact, addressing a significant limitation of current antibiotic treatments.
The background identifies critical unmet needs due to the risks, side effects, and diminishing effectiveness of currently available drugs for conditions like psoriasis, as well as the global rise of antibiotic resistance. Existing small-molecule drugs and biologics have patient-dependent side effects and can fail due to clinical variability, partly influenced by the microbiome. There is a need for new antibacterial agents effective against resistant bacteria and less prone to engendering resistance—requirements that the present invention addresses by providing antibacterial compounds with a novel mode of action and durability against resistance development.
Claims Coverage
The patent contains several independent claims that define the main inventive features related to novel antibacterial stilbene derivatives, their pharmaceutical compositions, methods of synthesis, and methods of antibacterial use.
Novel antibacterial stilbene derivatives of Formula I
The claims cover compounds of Formula I, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof, wherein various substituents (R1, R2, R3, R4, R5, A1, A2, A3, A4, A5, A1′, A2′, A3′, A4′, A5′, R, R6) are independently selected from an explicitly defined range of groups, including hydrogen, halogens, alkyl, acyl, aryl, heteroaryl, certain functional groups, and others as specified in the claim. This inventive feature encompasses new chemical entities with defined antibacterial activity.
Pharmaceutical composition comprising the antibacterial stilbene derivative
The claims provide for a pharmaceutical composition that contains at least one compound of Formula I, or a salt, solvate, tautomer, enantiomer, or geometric isomer thereof, in combination with at least one pharmaceutically acceptable excipient.
Enzymatic or biocatalytic synthesis of antibacterial stilbene derivatives
The claims cover methods of making a compound of Formula Ia, comprising contacting a compound of Formula IV (or variants as specified) with a medium comprising an organism (for example, a transformed organism containing the Plu1886 gene) and at least one metal salt, resulting in the production of the antibacterial stilbene dimer.
Methods of killing or disinfecting bacteria using the stilbene derivative
The claims include methods of killing or disinfecting bacteria by contacting a bacterial population with a compound of Formula I, or its permissible salt, solvate, tautomer, enantiomer, or geometric isomer, where the bacterial population may include antibiotic-resistant strains. The killing or disinfecting action is specified to occur after such contact, and encompasses use on living or non-living objects.
Methods for treating bacterial infections using the antibacterial stilbene derivative
The claims further include methods for treating bacterial infection in a subject by administering a therapeutically effective amount of a composition comprising the compound of Formula I (or permissible variants), together with at least one pharmaceutically acceptable excipient.
Methods for treating or ameliorating psoriasis or atopic dermatitis
The claims specify a method of treating or ameliorating psoriasis or atopic dermatitis by contacting the skin of a subject with a composition containing the compound of Formula I or its permissible variants. The composition may be topical or transdermal and include other active agents.
In summary, the patent claims novel antibacterial stilbene derivatives, pharmaceutical compositions thereof, biocatalytic and enzymatic synthesis methods, as well as broad methods for disinfecting, killing bacteria (including resistant strains), and treating bacterial infections and dermatological conditions such as psoriasis or atopic dermatitis.
Stated Advantages
The compounds of Formula I are able to kill a wide range of pathogenic bacteria, including multi-drug resistant strains such as MRSA and VRE.
Bacteria exposed to the compounds of Formula I do not develop resistance even after prolonged exposure, maintaining antibacterial efficacy over time.
The compounds can be used in methods to kill or disinfect bacteria on both living organisms and non-living objects.
The compounds activate the Nrf2 antioxidant signaling pathway more robustly than parent drug tapinarof, which is associated with cellular defense processes.
The invention provides alternative small molecule drugs for treating diseases such as psoriasis and atopic dermatitis with potentially fewer side effects.
Documented Applications
Treatment of bacterial infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE).
Disinfection or killing of bacteria on non-living objects or surfaces made of metals, ceramics, glass, wood, fabrics, rubber, plastic, polymers, or composites.
Topical or transdermal treatment or amelioration of psoriasis and/or atopic dermatitis in a subject.
Treatment of skin infections, ear infections, eye infections, bacterial vaginosis, bacterial meningitis, bacterial pneumonia, bacterial upper respiratory infections, thrush, urinary tract infection, bacterial gastroenteritis, impetigo, erysipelas, and cellulitis.
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