# US 9,751,851 B2 · Molecules and compositions that inhibit gram negative bacteria and their uses

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- Number: US 9,751,851 B2
- Document ID: US9751851B2
- Status: Granted
- Kind: B2
- Application number: 15/023,279
- Filed: 2014-09-19
- Published: 2016-12-22
- Granted: 2017-09-05
- Earliest claimed: 2013-09-20
- Assignees: The Trustees of Princeton University
- Applicants: The Trustees of Princeton University; Bonnie L. Bassler; Martin F. Semmelhack; Knut Drescher; Albert Siryaporn; Laura C. Miller; Colleen T. O'Loughlin
- Inventors: Bonnie L. Bassler; Martin F. Semmelhack; Knut Drescher; Albert Siryaporn; Laura C. Conrad-Miller; Colleen T. O'Loughlin
- Web page: https://patentgrep.com/patent/US9751851B2

## CPC

- C07D 333/32: Oxygen atoms
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 239/47: One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
- C07D 307/33: in position 2, the oxygen atom being in its keto or unsubstituted enol form
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)

## Abstract

Antivirulence strategies to combat Pseudomonas aeruginosa, are described. One strategy encompasses synthesis of a series of compounds that inhibit the production of pyocyanin, a redox-active virulence factor produced by this pathogen. A related strategy encompasses synthesis of compounds that inhibit the two P. aeruginosa quorum-sensing receptors, LasR and RhlR, inhibit production of pyocyanin, and inhibit biofilm formation.

## Claims

### Claim 1

A compound having the formula:
wherein
Py is a pyridine ring attached in the 2, 3, or 4 position and substituted with one or more additional substituents selected from the group consisting of alkyl, trifluoromethyl, methoxy, F, Cl and Br;
Aryl is a benzene ring with one or more additional substituents selected from the group consisting of methyl, trifluoromethyl, cyano, nitro, F, Cl, Br and methoxy;
X is O, NH, S or CH2; and
n is 0 to 4 —CH2— units.

### Claim 2

A compound having the formula:
where n=1 or 3.

### Claim 3 (depends on 1, 2)

A composition comprising the compound of claim 1 or 2.

### Claim 4 (depends on 1, 2)

A method for inhibiting gram negative bacteria biofilm production, virulence factor production, pyocyanin production, or quorum sensing, the method comprising the steps of:
providing a composition comprising a compound of claim 1 or 2; and
contacting at least one gram negative bacteria with the composition.

### Claim 5 (depends on 4)

The method of claim 4, wherein the gram negative bacteria is selected from Pseudomonas, Burkholderia cepaci C. violaceum, V. harveyi, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Haemophilus influenzae, Legionella pneumophila, Brucella, Francisella, Xanthomonas, Agrobacterium, Escherichia coli, Salmonella, Shigella, Proteus, or Yersinia pestisi.

### Claim 6 (depends on 5)

The method of claim 5, wherein the Pseudomonas is P. aeruginosa.

### Claim 7 (depends on 4)

The method of claim 4, wherein the composition inhibits the f LasR/RhlR receptor signaling of the at least one gram negative bacteria.

### Claim 8 (depends on 4)

The method of claim 4, wherein the subject is selected from a cow, a pig, a horse, a chicken, a cat, a dog, or a human.

### Claim 9 (depends on 4)

The method of claim 4, wherein the subject has an infection selected from a respiratory illness, pulmonary tract infection, a urinary tract infection, a catheter-associated infection, a blood infection, a middle ear infection, dental plaque, gingivitis, chronic sinusitis, endocarditis, eye infections, eye infections resulting from contact lens use, implanted device infection, a medical device infection, a central nervous infection, a gastrointestinal tract infection, a bone infection, a joint infection, an ear infection, an eye infection, a burn, a wound, an antibiotic resistant infection, is immunocompromised, is immunosuppressed, or has an opportunistic infection.

### Claim 10 (depends on 9)

The method of claim 9, wherein the medical device infection occurs in a patient having a catheter, a stent, a joint prosthesis, a prosthetic cardiac valve, on a ventilator or an intrauterine device.

### Claim 11 (depends on 9)

The method of claim 9, wherein the pulmonary tract infection is pneumonia.

### Claim 12 (depends on 9)

The method of claim 9, wherein the respiratory illness is Cystic Fibrosis.

### Claim 13 (depends on 12)

The method of claim 12, wherein the patient has both Cystic Fibrosis and pneumonia.

### Claim 14 (depends on 4)

The method of claim 4, wherein the composition is administered therapeutically.

### Claim 15 (depends on 4)

The method of claim 4, wherein the composition is administered prophylactically.

### Claim 16 (depends on 15)

The method of claim 15, wherein the subject is undergoing surgery, implantation of medical devices, or dental procedures.

### Claim 17 (depends on 4)

The method of claim 4, wherein the composition is co-administered with one or more additional drugs or other therapeutic agents.

### Claim 18 (depends on 17)

The method according to claim 17, wherein said one or more additional drugs or other therapeutic agents comprise one or more antibiotics.

### Claim 19 (depends on 4)

The method of claim 4, wherein the composition is administered topically.

### Claim 20 (depends on 4)

The method of claim 4, wherein the composition is administered intravenously.

### Claim 21 (depends on 4)

The method of claim 4, wherein the composition is administered intranasally.

### Claim 22 (depends on 4)

The method of claim 4, wherein the composition is used in an industrial setting.

### Claim 23 (depends on 22)

The method of claim 22, wherein the industrial setting is a work area, a medical instrument, a medical device, a chemical unit operation, a pipe, a sewage system, a pipeline, a tubing, or a filtration device.

### Claim 24 (depends on 23)

The method of claim 23, wherein the medical device is a catheter, a joint prosthesis, a prosthetic cardiac valve, a ventilator, a stent, or an intrauterine device.

### Claim 25 (depends on 23)

The method of claim 23, wherein the chemical unit operation comprises a microfluidic platform, a microelectromechanical system, a 3D printer, or a system for coating nanoparticle surfaces.