Antimicrobial compounds
Inventors
Stromberg, Roger • Ottoson, Hakan • Agerberth, Birgitta • Gudmundsson, Gudmundur • Miraglia, Erica • Nylen, Frank
Assignees
Publication Number
US-9957226-B2
Publication Date
2018-05-01
Expiration Date
2034-10-29
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Abstract
The invention provides compounds for use in treating microbial infection in an animal. Example compounds include Pyridin-3-ylmethyl (4-((2-aminophenyl)-carbamoyl)benzyl)carbamate (“Entinostat”). The compounds can act via induction of the innate antimicrobial peptide defense system, and stimulation of autophagy.
Core Innovation
The invention provides a new class of compounds, specifically benzoylated phenylenediamines or their derivatives, which act as powerful inducers of the innate antimicrobial peptide LL-37. These compounds effectively stimulate the innate antimicrobial peptide defense system, leading to secretion of antimicrobial peptides onto epithelial surfaces such as in the gastrointestinal tract or lung, thereby enhancing barrier function and treating microbial infections. This induction has been demonstrated in both a recombinant cell-line screening containing a human cathelicidin gene CAMP-luciferase construct and in normal colonic epithelial cell cultures (HT-29 cells).
The compounds of the present invention also stimulate autophagy, either via induction of LL-37 or independently, which further contributes to the removal of microbial infections. Unlike some previously known compounds that induce antimicrobial peptides through histone deacetylase (HDAC) inhibition, the new class of compounds shows no direct correlation between HDAC inhibition potency and LL-37 induction effectiveness, suggesting a different or additional mechanism of action.
The background problem addressed by the invention is the continual emergence of antibiotic resistance among bacterial pathogens and the limited pipeline of new antibiotics. Strengthening immune defenses by boosting endogenous “natural antibiotics” like antimicrobial peptides presents a novel or complementary approach to treating infectious diseases. While previous compounds like phenylbutyrate (PBA) and butyrate could induce antimicrobial peptides, the invention herein identifies more stable and potent compounds with longer half-lives and differing mechanisms, broadening the therapeutic options against microbial infections, including antibiotic-resistant strains.
Claims Coverage
The claims include two independent claims focusing on methods of treating microbial infections using specific compounds.
Method of treating microbial infection using compounds of formula (I)
Administering to an animal a compound defined by a specific chemical structure (formula (I)) characterized by various substituents including Q groups, linker L groups, and side chains as detailed in the specification.
Method of treating microbial infection using specific named compounds
Administering to an animal compounds selected from specific examples including N-(2-aminophenyl)benzamide, N-(2-aminophenyl)-4-methoxybenzamide, N-(2-aminophenyl)-4-nitrobenzamide, benzyl (4-((2-aminophenyl)carbamoyl)benzyl)carbamate, pyridin-3-ylmethyl (4-((2-aminophenyl)carbamoyl)benzyl)carbamate (Entinostat), and several other defined chemical compounds.
The independent claims focus on administering compounds of a defined chemical class or specific exemplified compounds to treat microbial infections by stimulating innate antimicrobial peptide responses and autophagy, covering broad structural variations and explicit compound examples.
Stated Advantages
The new class of compounds induces antimicrobial peptides at much lower concentrations than known compounds such as phenylbutyrate, demonstrating higher potency.
These compounds exhibit a mechanism of action distinct from histone deacetylase inhibition, indicating novel or additional pathways for innate immune stimulation.
They stimulate both the innate antimicrobial peptide defense system and autophagy, potentially leading to enhanced removal of microbial infections.
The compounds are more stable and have longer half-lives compared to previously known inducers like phenylbutyrate.
Documented Applications
Treatment and prevention of microbial infections including bacterial, viral, fungal, and protozoal diseases in humans and other animals.
Targeting infections by antibiotic-resistant bacterial strains such as Yersinia, Salmonella, Shigella, Campylobacter, Clostridium, Helicobacter, Mycobacterium, Pseudomonas, Haemophilus, Moraxella, Escherichia, Neisseria, Streptococcus, and Staphylococcus.
Treatment of infections of organs with epithelial surfaces having host defense peptide secretion systems including the gastrointestinal tract, lung, trachea, urinary tract, kidney, genital tract, eye, skin, and blood.
Specific diseases mentioned include pneumonia, tuberculosis, shigellosis, traveller's diarrhoea, dysentery, viral gastroenteritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, gastrointestinal cancers, various eye infections, urinary and genital infections, respiratory tract infections including bronchitis and influenza, and skin infections such as boils and cellulitis.
Use in combination therapies with antibiotics, vitamin D compounds, and isoleucine or analogs to enhance treatment efficacy and potentially reduce antibiotic resistance development.
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