Product and Process for Inhibition of Biofilm Development

• US 20130224200A1
• Filed: 10/12/2012
• Published: 08/29/2013
• Est. Priority Date: 08/06/2004
• Status: Active Grant

• Current Assignee: National Jewish Health
• Original Assignee: National Jewish Health
• Inventors: Nick, Jerry A., Walker, Travis S., Worthen, G. Scott
• Granted Patent: US 8,901,167 B2
• Time in Patent Office: Days
• US Class Current: 424/135.1
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/432 Inhibitors, antagonists A61L2300/402 - A61L2300/43 take precedence
• CPC Class Codes: A61L 29/16 Biologically active materials, e.g. therapeutic substances A61L29/048 takes precedence

Abstract

Disclosed are compositions and methods for the inhibition of biofilm formation or reduction of existing or developing biofilms in a patient. These methods also inhibit the aggregation of bacteria that form biofilms in the airways. The methods include administering to a subject that has or is at risk of developing biofilms a compound or formulation that inhibits the formation or polymerization of actin microfilaments or depolymerizes actin microfilaments at or proximal to the site of biofilm formation. Such a compound can be administered in combination with a compound or formulation that inhibits the accumulation or activity of cells that are likely to undergo necrosis at or proximal to the site of biofilm formation (i.e., neutrophils). The methods and compositions can further include the use of anti-DNA and/or anti-mucin compounds, as well as other therapeutic compounds and compositions.

Claims

1-31. -31. (canceled)

32. A method to inhibit biofilm formation or reduce biofilms in a subject, the biofilm or biofilms forming as a result of the contact of the subject with a medical device, a graft, a catheter, a stent, a wound dressing, or a prosthesis;

being associated with the presence of necrotic cells; and

being produced by a microorganism that has enhanced biofilm formation in the presence of said necrotic cells, the method comprising administering to a subject that has or is developing biofilms, a compound that inhibits the formation or polymerization of actin microfilaments or depolymerizes actin microfilaments at or proximal to the site of biofilm formation or the site of infection by said microorganism wherein inhibition of the formation or polymerization of actin microfilaments or the depolymerization of actin filaments inhibits biofilm formation or reduces biofilms in the subject, wherein the compound is selected from the group consisting of latrunculins and swinholides.

33. The method of claim 32, wherein the actin microfilaments are formed from the content of said necrotic cell that undergoes necrosis at or proximal to the site of biofilm formation or the site of infection by said microorganism that forms biofilms.

34. The method of claim 33, wherein the necrotic cell is a neutrophil.

35. The method of claim 32, further comprising administering to the subject an anti-DNA compound.

36. The method of claim 32, further comprising administering to a subject a compound that inhibits accumulation of, inhibits necrosis of, or inhibits release of the cellular contents of, cells that undergo necrosis, at or proximal to the site of biofilm formation or the site of infection by a microorganism that forms biofilms.

37. The method of claim 36, wherein the cells that undergo necrosis are neutrophils.

38. The method of claim 37, wherein the compound that inhibits accumulation of, inhibits necrosis of, or inhibits release of the cellular contents of, cells that undergo necrosis, at or proximal to the site of biofilm formation or the site of infection by said microorganism that forms biofilms inhibits:

the adherence of neutrophils at or proximal to the site of biofilm formation or the site of said infection, the migration of neutrophils to or proximal to the site of biofilm formation or the site of said infection, or the sensing or response to chemoattractants at or proximal to the site of biofilm formation or the site of said infection by neutrophils, or inhibits the activity or release of a cytokine, chemokine or chemoattractant that attracts or enhances neutrophil activity.

39. The method of claim 36, wherein the compound that inhibits accumulation of, inhibits necrosis of, or inhibits release of the cellular contents of, cells that undergo necrosis, at or proximal to the site of biofilm formation or the site of infection by said microorganism that forms biofilms is an anti-inflammatory compound.

40. The method of claim 36, further comprising administering to the subject an anti-DNA compound.

41. The method of claim 32, further comprising administering to the subject an anti-mucin compound.

42. The method of claim 32, further comprising administering to the subject a compound for treatment of a disease or condition associated with said biofilm formation.

43. The method of claim 32, wherein the compound is administered when said biofilm formation is diagnosed or suspected.

44. The method of claim 32, wherein the compound is administered prior to the treatment of the subject with a medical device, a graft, a catheter, a stent, a wound dressing, or a prosthesis that may cause said biofilm to form in the patient.

45. The method of claim 32, wherein the compound is administered with a pharmaceutically acceptable carrier.

46. The method of claim 32, wherein the compound is administered directly to or proximal to the site of said biofilm formation or the site of infection by a microorganism that forms biofilms.

47. The method of claim 32, wherein the compound is administered to the lung or airways of the subject.

48. The method of claim 32, wherein the compound is applied to a prosthetic graft or administered to the subject receiving the graft prior to or during the implantation or utilization of the graft.

49. The method of claim 32, wherein the compound is applied to a catheter prior to or during use of the catheter by a subject.

50. The method of claim 32, wherein the compound is applied to the site of a wound or to the wound dressing when the wound is treated.

51. The method of claim 32, wherein the compound is applied to a medical device that contacts a subject tissue surface prior to or during use of the medical device by a subject.

52. The method of claim 32, wherein the biofilm forms in connection with a disease or condition in an organ, tissue or body system.

53. The method of claim 32, wherein the biofilm forms on a surface of a tissue, organ or bodily part proximal to or at the site of the application of the medical device, graft, catheter, stent, wound dressing, or prosthesis.

54. The method of claim 32, wherein the biofilm forms in connection with a condition selected from the group consisting of:

catheter-related infection (kidney, vascular, peritoneal), medical device-related infections, orthopedic implant infection, wounds, and biliary stents, wherein the condition is associated with the presence of necrotic cells at the site of biofilm formation.

55. The method of claim 32, wherein the microorganism is Pseudomonas aeruginosa.

56. The method of claim 32, wherein the microorganism is a bacterium.

57. The method of claim 32, wherein the microorganism is Burkholderia.

58. A method to inhibit biofilm formation or reduce biofilms in a subject, the biofilm or biofilms forming as a result of the contact of the subject with a medical device, a graft, a catheter, a stent, a wound dressing, or a prosthesis, and being associated with the presence of necrotic cells;

the biofilm or biofilms being produced by a microorganism that has enhanced biofilm formation in the presence of said necrotic cells, the method comprising administering to a subject that has or is developing said biofilms;

(1) a first compound that inhibits the formation or polymerization of actin microfilaments or depolymerizes actin microfilaments, wherein the first compound is selected from the group consisting of latrunculins, and swinholides; and

(2) an anti-DNA compound, wherein the first compound and the anti-DNA compound are administered at or proximal to the site of said biofilm formation or the site of infection by said microorganism, wherein inhibition of the formation or polymerization of actin microfilaments or the depolymerization of actin filaments and the administration of the anti-DNA compound, inhibit biofilm formation or reduce biofilms in the subject.