Molecules and compositions that inhibit gram negative bacteria and their uses
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.
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 CH 2 ; and
n is 0 to 4 —CH 2 — units.
2. A compound having the formula:
where n=1 or 3.
3. A composition comprising the compound of claim 1 or 2 .
4. 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.
5. 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.
6. The method of claim 5 , wherein the Pseudomonas is P. aeruginosa.
7. The method of claim 4 , wherein the composition inhibits the f LasR/RhlR receptor signaling of the at least one gram negative bacteria.
8. 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.
9. 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.
10. 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.
11. The method of claim 9 , wherein the pulmonary tract infection is pneumonia.
12. The method of claim 9 , wherein the respiratory illness is Cystic Fibrosis.
13. The method of claim 12 , wherein the patient has both Cystic Fibrosis and pneumonia.
14. The method of claim 4 , wherein the composition is administered therapeutically.
15. The method of claim 4 , wherein the composition is administered prophylactically.
16. The method of claim 15 , wherein the subject is undergoing surgery, implantation of medical devices, or dental procedures.
17. The method of claim 4 , wherein the composition is co-administered with one or more additional drugs or other therapeutic agents.
18. The method according to claim 17 , wherein said one or more additional drugs or other therapeutic agents comprise one or more antibiotics.
19. The method of claim 4 , wherein the composition is administered topically.
20. The method of claim 4 , wherein the composition is administered intravenously.
21. The method of claim 4 , wherein the composition is administered intranasally.
22. The method of claim 4 , wherein the composition is used in an industrial setting.
23. 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.
24. 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.
25. 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.