Product and process for inhibition of biofilm development

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.

1 . A method to inhibit biofilm formation or reduce biofilms in a subject, comprising administering to a subject that has or is at risk of 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 a microorganism that forms biofilms.  
     
     
         2 . The method of  claim 1 , wherein the actin microfilaments are formed from the content of a cell that undergoes necrosis at or proximal to the site of biofilm formation or the site of infection by a microorganism that forms biofilms.  
     
     
         3 . The method of  claim 2 , wherein the cell is a neutrophil.  
     
     
         4 . The method of Clam 1, further comprising administering to the subject an anti-DNA compound.  
     
     
         5 . The method of  claim 1 , 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.  
     
     
         6 . The method of  claim 5 , wherein the cells that undergo necrosis are neutrophils.  
     
     
         7 . The method of  claim 6  wherein the compound inhibits the adherence of, migration to, or the sensing or response to chemoattractants by neutrophils, or inhibits the activity or release of a cytokine, chemokine or chemoattractant that attracts or enhances neutrophil activity.  
     
     
         8 . The method of  claim 5 , wherein the compound is an anti-inflammatory compound.  
     
     
         9 . The method of  claim 5 , further comprising administering to the subject an anti-DNA compound.  
     
     
         10 . The method of  claim 1 , further comprising administering to the subject an anti-mucin compound.  
     
     
         11 . The method of  claim 1 , further comprising administering to the subject a compound for treatment of a disease or condition associated with biofilm formation.  
     
     
         12 . The method of  claim 1 , wherein the compound is administered when a disease or condition associated with biofilm formation is diagnosed or suspected.  
     
     
         13 . The method of  claim 1 , wherein the compound is administered prior to the treatment of the subject with a process that may cause a biofilm to form in the patient.  
     
     
         14 . The method of  claim 1 , wherein the compound is administered with a pharmaceutically acceptable carrier.  
     
     
         15 . The method of  claim 1 , wherein the compound is administered directly to or proximal to the site of biofilm formation or potential therefore.  
     
     
         16 . The method of  claim 1 , wherein the compound is administered to the lung or airways of the subject.  
     
     
         17 . The method of  claim 1 , 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.  
     
     
         18 . The method of  claim 1 , wherein the compound is applied to a catheter prior to or during use of the catheter by a subject.  
     
     
         19 . The method of  claim 1 , wherein the compound is applied to the site of a wound or to the wound dressing when the wound is treated.  
     
     
         20 . The method of  claim 1 , 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.  
     
     
         21 . The method of  claim 1 , wherein the biofilm forms in connection with a disease or condition in an organ, tissue or body system.  
     
     
         22 . The method of  claim 1 , wherein the biofilm forms on a surface of a tissue, organ or bodily part.  
     
     
         23 . The method of  claim 1 , wherein the biofilm forms in connection with a disease or condition selected from the group consisting of: infectious kidney stones, cystitis, catheter-related infection (kidney, vascular, peritoneal), medical device-related infections, prostatitis, dental caries, chronic otitis media, cystic fibrosis, bronchiectasis, bacterial endocarditis, Legionnaire's disease, orthopedic implant infection, osteomyelitis, wounds, acne, and biliary stents.  
     
     
         24 . The method of  claim 1 , wherein the subject has or is suspected of having cystic fibrosis.  
     
     
         25 . The method of  claim 1 , wherein the microorganism is  Pseudomonas aeruginosa.    
     
     
         26 . A method to inhibit biofilm formation or reduce biofilms in a subject, comprising administering to a subject that has or is at risk of developing biofilms: (1) a first compound that inhibits the formation or polymerization of actin microfilaments or depolymerizes actin microfilaments; and (2) an anti-DNA compound, wherein the first compound and the anti-DNA compound are administered at or proximal to the site of biofilm formation or the site of infection by a microorganism that forms biofilms.  
     
     
         27 . A composition for inhibiting biofilm formation or reducing biofilms in a subject, comprising: (1) a first compound that inhibits the formation or polymerization of actin microfilaments or depolymerizes actin microfilaments at or proximal to the site of biofilm formation; and (2) a second compound that is an anti-DNA compound.  
     
     
         28 . The composition of  claim 27 , further comprising a compound that inhibits the accumulation of, necrosis of, or release of the cellular contents of, neutrophils at or proximal to the site of biofilm formation, and a carrier suitable for application to the site of biofilm formation.  
     
     
         29 . A composition for inhibiting biofilm formation or reducing biofilms in a subject, comprising: (1) a first compound that inhibits the formation or polymerization of actin microfilaments or depolymerizes actin microfilaments at or proximal to the site of biofilm formation; and (2) a second compound that inhibits the accumulation of, necrosis of, or release of the cellular contents of, neutrophils at or proximal to the site of biofilm formation, and a carrier suitable for application to the site of biofilm formation.  
     
     
         30 . A method to identify a compound that inhibits necrotic cell-enhanced biofilm formation or reduces necrotic cell-enhanced biofilms in a subject, comprising: 
 a) contacting a putative inhibitory compound with a microbial culture in the presence and absence of a population of cells or a lysate thereof, wherein the microbial culture forms biofilms and is in a planktonic state prior to contact with the putative inhibitory compound, and wherein the population of cells undergoes necrosis in the presence of the microbial cells; and    b) measuring biofilm formation after contact with the putative regulatory compound as compared to in the absence of the compound and as compared to in the presence and absence of the population of cells or lysate thereof; wherein a decrease in biofilm formation in the presence of the putative regulatory compound and the presence of the population of cells or lysate thereof, as compared to in the absence of the population of cells or lysate thereof and as compared to in the absence of the putative regulatory compound, indicates that the putative regulatory compound inhibits necrotic cell-enhanced biofilm formation or reduces necrotic cell-enhanced biofilms.    
     
     
         31 . The method of  claim 30 , wherein the population of cells is a population of neutrophils.