# US 2020/0368218 A1 · Repurposing compounds for the treatment of infections and for modulating the composition of the gut microbiome

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- Number: US 2020/0368218 A1
- Document ID: US20200368218A1
- Status: Published application
- Kind: A1
- Application number: 16/966,307
- Filed: 2019-02-13
- Published: 2020-11-26
- Earliest claimed: 2018-02-13
- Assignees: European Molecular Biology Laboratory
- Applicants: European Molecular Biology Laboratory
- Inventors: MIHAELA PRUTEANU; LISA MAIER; MICHAEL KUHN; PEER BORK; ATHANASIOS TYPAS; KIRAN RAOSAHEB PATIL; GEORG ZELLER
- Web page: https://patentgrep.com/patent/US20200368218A1

## CPC

- A61K 31/4422: 1,4-Dihydropyridines, e.g. nifedipine, nicardipine
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to agents and compositions for the modification of the growth of bacterial cells. Thus, the compounds of the present invention are useful for the prevention and/or treatment of a disease in a subject. In particular, the present invention relates to the field of repurposing pharmaceutical compounds for treatment strategies of infectious diseases, gastrointestinal disorders, inflammatory diseases, proliferative diseases, metabolic disorders, cardiovascular diseases, and immunological diseases. Some of the compounds of the present invention demonstrate high specificity in inhibiting the growth of single bacterial species. Such compounds enable narrow-spectrum antibacterial therapies, constituting a major effort of current and future drug development strategies in order to reduce side effects of antibacterial treatment plans. Particularly interesting compounds of this invention are effective against pathobiological species such as Clostridium difficile, Clostridium perfingens, Fusobacterium nucleatum, and an enterotoxigenic strain of Bacteroides fragilis. Other compounds of the present invention reveal a strong inhibitory effect on a broad spectrum of bacterial species. Such compounds are useful for broad-spectrum antibiotic therapies of infections with unknown causative infecting bacterial species. Both types of compounds, especially the ones with narrow-spectrum antibacterialactivity, can further be used for modulating the microbiome composition and targeting species associated with dysbiosis and disease.

## Claims

### Claim 1

A method for modifying growth of bacterial cells, wherein said method comprises contacting bacterial cells with a compound selected from a Ca-channel inhibitor, Tribenoside, Telmisartan, Azathioprine, Mercaptopurine, Mifepristone, Montelukast, Fentiazac, Meclozine dihydrochloride, Carbenoxolone, Gliquidone, Alfacalcidol, Acarbose, Ethacrynic acid, Chlorpromazine hydrochloride, Cyclosporin A, Flufenamic acid, Aripiprazole, Idebenone, Thioguanosine, Thyroxine (L), Gemcitabine, Folic acid, Etretinate, Paclitaxel, Phenindione, Mometasone furoate, Azacytidine-5, Luteolin, Metixene hydrochloride, Protriptyline hydrochloride, Toltrazuril, Tolnaftate, Meclofenamic acid, Prenylamine lactate, Diacerein, Dicumarol, Clemizole hydrochloride, Loratadine, Troglitazone, Tiratricol, Bepridil hydrochloride, Estradiol Valerate, Anthralin, Aprepitant, Amiodarone hydrochloride, Ethopropazine hydrochloride, Astemizole, Methiothepin maleate, pharmaceutically acceptable salts thereof, and derivatives thereof.

### Claim 2 (depends on 1)

The method according to claim 1, wherein said bacterial cells are selected from cells of Gram-positive bacteria, Gram-negative bacteria, Enterobacter, Staphylococcus, Streptococcus, Pseudomonas, Escherichia, Salmonella, Helicobacter, Neisseria, Campylobacter, Chlamydia, Clostridia, Citrobacter, Vibrio, Treponema, Mycobacterium, Klebsiella, Actinomyces, Bacteroides, Bordetella, Borrelia, Brucella, Corynebacteria, Diplococcus, Fusobacterium, Leptospira, Listeria, Pasteurella, Proteus, Rickettsia, Shigella, Yersinia, Parabacteroides, Odoribacter, Faecalibacteria, Collinsella, Eggerthella, Lactonifactor, Pediococcus, Leuconostoc, Lactococcus, Roseburia, Coliform, Bacillus, Franscicella, Acinetobacter, Legionella, Actinobacillus, Coxiella, Kingella kingae, Haemophilus, Bifidobacteria, Mobiluncus, Prevotella, Akkermansia, Bilophila, Blautia, Coprococcus, Dorea, Eubacteria, Lactobacillus, Ruminococcus, Veillonella, Enterococcus, and combinations thereof, optionally wherein said bacteria are antibiotic-resistant bacteria and/or multi-drug resistant bacteria.

### Claim 3 (depends on 1)

The method according to claim 1, wherein a therapeutically effective amount of said compound is administered to a subject, thereby modifying the growth of bacterial cells in said subject, wherein said modifying results in the prevention and/or treatment of a disease in said subject and/or in the modification of the composition of the microbiome of said subject.

### Claim 4 (depends on 3)

The method according to claim 3, wherein said disease is selected from an infectious disease, a gastrointestinal disorder, an inflammatory disease, a proliferative disease, a metabolic disorder, a cardiovascular disease, and an immunological disease.

### Claim 5 (depends on 1)

The method according to claim 1, wherein said compound is in the form of a tablet, coated tablet, effervescent tablet, capsule, powder, granulate, sugar-coated tablet, lozenge, pill, ampoule, drop, suppository, emulsion, ointment, gel, tincture, paste, cream, moist compress, gargling solution, plant juice, nasal agent, inhalation mixture, aerosol, mouthwash, mouth spray, nose spray or room spray.

### Claim 6 (depends on 1)

The method according to claim 1, wherein said compound modifies the growth of bacterial cells of a spectrum of bacterial species selected from Gram-positive bacteria, Gram-negative bacteria, Enterobacter, Staphylococcus, Streptococcus, Pseudomonas, Escherichia, Salmonella, Helicobacter, Neisseria, Campylobacter, Chlamydia, Clostridia, Citrobacter, Vibrio, Treponema, Mycobacterium, Klebsiella, Actinomyces, Bacteroides, Bordetella, Borrelia, Brucella, Corynebacteria, Diplococcus, Fusobacterium, Leptospira, Listeria, Pasteurella, Proteus, Rickettsia, Shigella, Yersinia, Parabacteroides, Odoribacter, Faecalibacteria, Collinsella, Eggerthella, Lactonifactor, Pediococcus, Leuconostoc, Lactococcus, Roseburia, Conform, Bacillus, Franscicella, Acinetobacter, Legionella, Actinobacillus, Coxiella, Kingella kingae, Haemophilus, Bifidobacteria, Mobiluncus, Prevotella, Akkermansia, Bilophila, Blautia, Coprococcus, Dorea, Eubacteria, Lactobacillus, Ruminococcus, Veillonella, and Enterococcus, wherein said spectrum consists of less than 20 bacterial species.

### Claim 7 (depends on 6)

The method according to claim 6, wherein said bacteria are Clostridia selected from the group consisting of C. difficile, C. butyricum, C. perfringens, C. novyi, C. septicum, C. botulinum, C. tetani, C. haemolyticum, C. carnis, C. histolyticum, C. sordellii, C. septicum, C. tertium, C. sporogenes, C. ramosum, C. inocuum, C. paraputrificum, C. cadaveris, C. bifermentans, C. fallax, and C. clostridioforme, and combinations thereof.

### Claim 8 (depends on 6)

The method according to claim 6, wherein said compound is a Ca-channel inhibitor.

### Claim 9 (depends on 6)

The method according to claim 6, wherein said bacterial species is C. perfringens, and said compound is selected from Alfacalcidol, Acarbose, Ethacrynic acid, Chlorpromazine hydrochloride, Cyclosporin A, Idebenone, Thioguanosine, Gemcitabine, Etretinate, Paclitaxel, Phenindione, Azacytidine-5, pharmaceutically acceptable salts thereof, and derivatives thereof

### Claim 10 (depends on 6)

The method according to claim 6, wherein said bacterial species is Fusobacterium nucleatum, and wherein said compound is selected from Luteolin, pharmaceutically acceptable salts thereof, and derivatives thereof.

### Claim 11 (depends on 6)

The method according to claim 6, wherein said bacterial species is an enterotoxigenic strain of Bacteroides fragilis, and wherein said compound is selected from Metixene hydrochloride, Protriptyline hydrochloride, Toltrazuril, Acarbose, Ethacrynic acid, Tolnaftate, Cilnidipine, Meclofenamic acid, Prenylamine lactate, pharmaceutically acceptable salts thereof, and derivatives thereof

### Claim 12

(canceled)

### Claim 13 (depends on 1)

The method according to claim 1, wherein said compound enhances the growth of bacterial cells of bacterial species selected from Lactobacillus, Bifidobacterium, Enterococcus, Streptococcus, Pediococcus, Leuconostoc, Bacillus, Eschericha, Lactococcus, and combinations thereof.

### Claim 14

A pharmaceutical composition for use in the prevention and/or treatment of a disease in a subject and/or in the modification of the composition of the microbiome of a subject, comprising
i) a compound selected from a Ca-channel inhibitor, Tribenoside, Telmisartan, Azathioprine, Mercaptopurine, Mifepristone, Montelukast, Fentiazac, Meclozine dihydrochloride, Carbenoxolone, Gliquidone, Alfacalcidol, Acarbose, Ethacrynic acid. Chlorpromazine hydrochloride. Cyclosporin A, Flufenamic acid, Aripiprazole, Idebenone, Thioguanosine, Thyroxine (L), Gemcitabine, Folic acid, Etretinate, Paclitaxel. Phenindione, Mometasone furoate, Azacvtidine-5, Luteolin. Metixene hydrochloride, Protriptyline hydrochloride, Toltrazuril, Tolnaftate. Meclofenamic acid, Prenylamine lactate, Diacerein, Dicumarol, Clemizole hydrochloride, Loratadine, Troglitazone, Tiratricol, Bepridil hydrochloride, Estradiol Valerate, Anthralin, Aprepitant, Amiodarone hydrochloride. Ethopropazine hydrochloride, Astemizole. Methiothepin maleate. pharmaceutically acceptable salts thereof, and derivatives thereof; and
ii) a pharmaceutically acceptable additive, carrier, diluent, solvent, filter, lubricant, excipient, binder, and/or stabilizer.

### Claim 15

(canceled)

### Claim 16 (depends on 3)

The method according to claim 3, wherein the said subject is a mouse, rat, guinea pig, rabbit, cat, dog, monkey, or human.

### Claim 17 (depends on 4)

The method according to claim 4, wherein the disease is selected from an infection of the gastrointestinal tract, an infection of the urogenital tract, an infection of the upper lower respiratory tract, an infection of the lower respiratory tract, rhinitis, tonsillitis, pharyngitis, dysbiosis, bronchitis, pneumonia, an infection of the inner organs, nephritis, hepatitis, peritonitis, endocarditis, meningitis, osteomyelitis, an infection of the eyes, an infection of the ears, a cutaneous infection, a subcutaneous infection, an infection after burn, diarrhea, colitis, pseudomembranous colitis, a skin disorder, toxic shock syndrome, bacteremia, sepsis, pelvic inflammatory disease, vaginosis, an infection of the central nervous system, wound infection, intra-abdominal infection, intravascular infection, bone infection, joint infection, acute bacterial otitis media, pyelonephritis, deep-seated abscess, tuberculosis, a gastrointestinal motility disorder, irritable bowel syndrome, constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dysbiosis, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn's disease, colitis, ulcerative colitis, inflammatory bowel disease, diverticulitis, gluten intolerance and/or lactose intolerance, obesity, stomach rumble, small intestinal bacterial overgrowth (SIBO), small intestinal fungal overgrowth (SIFO), meteorism, flatulence, Crohn's disease, inflammatory bowel disease, ulcerative colitis, collagenous-, lymphocytic-, ischemic-, diversion- and/or indeterminate colitis, periodontal disease, chronic fatigue syndrome, myalgic encephalomyelitis, Behçet's disease, atherosclerosis, rheumatoid arthritis, gastric cancer and colorectal cancer.

### Claim 18 (depends on 3)

The method according to claim 3, wherein wherein said compound is administered to said subject by oral, intranasal, topical, rectal, bronchial, vaginal, or parenteral administration.

### Claim 19 (depends on 6)

The method according to claim 6, wherein said compound is selected from a Ca-channel inhibitor, Tribenoside, Telmisartan, Azathioprine, Mercaptopurine, Mi fepristone, Montelukast, Fentiazac, Meclozine dihydrochloride, Carbenoxolone, Gliquidone, Alfacalcidol, Acarbose, Ethacrynic acid, Chlorpromazine hydrochloride, Cyclosporin A, Flufenamic acid, Aripiprazole, Idebenone, Thioguanosine, Thyroxine (L), Gemcitabine, Folic acid, Etretinate, Paclitaxel, Phenindione, Mometasone furoate, Azacytidine-5, Luteolin, Metixene hydrochloride, Protriptyline hydrochloride, Toltrazuril, Tolnaftate, Meclofenamic acid, Prenylamine lactate, pharmaceutically acceptable salts thereof, and derivatives thereof.

### Claim 20 (depends on 8)

The method according to claim 8, wherein said Ca-channel inhibitor is selected from a dihyropyridine, Fendiline hydrochloride, pharmaceutically acceptable salts thereof, and derivatives thereof.

### Claim 21 (depends on 8)

The method according to claim 8, wherein said dihyropyridine or said derivative thereof is selected from Lacidipine, Cilnidipine, Amlodipine, and pharmaceutically acceptable salts thereof.