Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics

Abstract

Compositions and methods for treating infections, especially bacterial infections, are provided. Indolicidin peptide analogues containing at least two basic amino acids are prepared. The analogues are administered as modified peptides, preferably containing photo-oxidized solubilizer.

1 - 3 . (canceled) 
     
     
         4 . A method of treating or preventing a microbial infection, comprising administering to a patient a therapeutically effective amount of a composition comprising at least one indolicidin analogue of up to 35 amino acids that comprises one of the following sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 25) 
                 
                     
                   Lys Arg Arg Trp Pro Trp Trp Pro Trp Lys  
                 
                     
                     
                 
                     
                   Lys Leu Ile; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 23) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                   Arg Lys; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 46) 
                 
                     
                   Lys Arg Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                   Leu Ile; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 47) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                     
                 
                     
                   Arg Lys Ile Met Ile Leu Lys Lys Ala Gly  
                 
                     
                     
                 
                     
                   Ser; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 24) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg  
                 
                     
                     
                 
                     
                   Arg Lys Met Ile Leu Lys Lys Ala Gly Ser; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 48) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                   Arg Lys Asp Met Ile Leu Lys Lys Ala Gly  
                 
                     
                     
                 
                     
                   Ser; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 26) 
                 
                     
                   Trp Arg Ile Trp Lys Pro Lys Trp Arg Leu  
                 
                     
                     
                 
                     
                   Pro Lys Trp; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 59) 
                 
                     
                   Ile Leu Lys Lys Trp Val Trp Trp Pro Trp   
                 
                     
                     
                 
                     
                   Arg Arg Lys; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 27) 
                 
                     
                   Ile Leu Arg Trp Val Trp Trp Val Trp Arg   
                 
                     
                     
                 
                     
                   Arg Lys; 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 60) 
                 
                     
                   Lys Arg Arg Trp Val Trp Trp Val Trp Arg   
                 
                     
                     
                 
                     
                   Leu Ile. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         5 . The method of  claim 4 , wherein the indolicidin analogue comprises the sequence of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO:23). 
     
     
         6 . The method of  claim 4 , wherein the amino acid sequence of the indolicidin analogue consists of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO:23). 
     
     
         7 . The method of  claim 4 , wherein the microbial infection is due to a bacterium and wherein the composition is administered ex vivo. 
     
     
         8 . The method of  claim 7 , wherein the composition is administered to the skin of the patient. 
     
     
         9 . The method of  claim 4 , wherein the microbial infection is associated with nasal colonization. 
     
     
         10 . The method of  claim 9 , wherein the composition is administered by aerosolization or spray. 
     
     
         11 . The method of  claim 4 , wherein the microbial infection is a burn-related infection. 
     
     
         12 . The method of  claim 4 , wherein the microbial infection is a surgical wound infection. 
     
     
         13 . The method of  claim 4 , wherein the composition is a gel. 
     
     
         14 . The method of  claim 6 , wherein the microbial infection is associated with nasal colonization. 
     
     
         15 . The method of  claim 14 , wherein the composition is administered by aerosolization or spray. 
     
     
         16 . The method of  claim 6 , wherein the microbial infection is a burn-related infection. 
     
     
         17 . The method of  claim 6 , wherein the microbial infection is a surgical wound infection. 
     
     
         18 . The method of  claim 6 , wherein the composition is a gel. 
     
     
         19 . The method of  claim 4 , wherein the composition further comprises an antibiotic. 
     
     
         20 . The method of  claim 4 , further comprising the step of administering an antibiotic. 
     
     
         21 . The method of  claim 20 , wherein the antibiotic is minocycline, rifampin, cefazolin, vancomycin, teicoplanin, or a beta lactam. 
     
     
         22 . The method of  claim 4 , wherein the microbial infection is due to a bacterium. 
     
     
         23 . The method of  claim 22 , wherein the bacterium is antibiotic resistant. 
     
     
         24 . The method of  claim 23 , wherein the antibiotic resistant bacteria is resistant to at least one of a penicillin, a cephalosporin, a fluoroquinolone, a macrolide, or an aminoglycoside. 
     
     
         25 . The method of  claim 23 , wherein the antibiotic resistant bacteria is resistant to at least one of a tetracycline, a quinolone, a glycopeptide, a monobactam, a carbacephem, a carbapenem, or a cephamycin. 
     
     
         26 . The method of  claim 23 , wherein the antibiotic resistant bacteria is resistant to at least one of methicillin, vancomycin, teicoplanin, ciprofloxacin, clindamycin, ampicillin, erythromycin, amikacin, ceftriaxone, gentamicin, mupirocin, piperacillin, or tobramycin. 
     
     
         27 . A method of inhibiting or preventing growth of a bacterium on a surface of an object, comprising coating the surface with a therapeutically effective amount of a composition comprising at least one indolicidin analogue of up to 35 amino acids that comprises one of the following sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 25) 
                 
                     
                   Lys Arg Arg Trp Pro Trp Trp Pro Trp Lys   
                 
                     
                     
                 
                     
                   Lys Leu Ile; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 23) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                   Arg Lys; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 46) 
                 
                     
                   Lys Arg Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                   Leu Ile; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 47) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg   
                 
                     
                     
                 
                     
                   Arg Lys Ile Met Ile Leu Lys Lys Ala Gly  
                 
                     
                     
                 
                     
                   Ser; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 24) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg  
                 
                     
                     
                 
                     
                   Arg Lys Met Ile Leu Lys Lys Ala Gly Ser; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 48) 
                 
                     
                   Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg 
                 
                     
                     
                 
                     
                   Arg Lys Asp Met Ile Leu Lys Lys Ala Gly  
                 
                     
                     
                 
                     
                   Ser; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 26) 
                 
                     
                   Trp Arg Ile Trp Lys Pro Lys Trp Arg Leu   
                 
                     
                     
                 
                     
                   Pro Lys Trp; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 59) 
                 
                     
                   Ile Leu Lys Lys Tip Val Trp Trp Pro Trp   
                 
                     
                     
                 
                     
                   Arg Arg Lys; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 27) 
                 
                     
                   Ile Leu Arg Trp Val Trp Trp Val Trp Arg  
                 
                     
                     
                 
                     
                   Arg Lys; 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 60) 
                 
                     
                   Lys Arg Arg Trp Val Trp Trp Val Trp Arg   
                 
                     
                     
                 
                     
                   Leu Ile. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         28 . The method of  claim 27 , wherein the indolicidin analogue comprises the sequence of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO:23). 
     
     
         29 . The method of  claim 27 , wherein the amino acid sequence of the indolicidin analogue consists of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO:23). 
     
     
         30 . The method of  claim 27 , further comprising the step of contacting the surface of the object with an antibiotic. 
     
     
         31 . The method of  claim 30 , wherein the antibiotic is minocycline, rifampin, cefazolin, vancomycin, teicoplanin, or a beta lactam. 
     
     
         32 . The method of  claim 27 , wherein the bacterium is antibiotic resistant. 
     
     
         33 . The method of  claim 32 , wherein the antibiotic resistant bacteria is resistant to at least one of a penicillin, a cephalosporin, a fluoroquinolone, a macrolied, an aminoglycoside, a tetracycline, a quinolone, a glycopeptide, a monobactam, a carbacephem, a carbapenem, or a cephamycin. 
     
     
         34 . The method of  claim 27 , wherein the object is a stent, tube, probe, cannula, catheter, synthetic vascular graft, blood monitoring device, artificial heart valve, or needle. 
     
     
         35 . The method of  claim 27 , wherein the object is a tube. 
     
     
         36 . The method of  claim 27 , wherein the object is a medical device. 
     
     
         37 . The method of  claim 36 , wherein the medical device is a catheter. 
     
     
         38 . The method of  claim 36 , wherein the medical device is an intravascular device. 
     
     
         39 . The method of  claim 27 , wherein the bacteria is a Gram-negative bacteria selected from the group consisting of  Enterobacter  sp.,  E. coli, Klebsiella  sp., and  Acinetobacter  sp. 
     
     
         40 . The method of  claim 27 , wherein the bacteria is a Gram-positive bacteria selected from the group consisting of  S. aureus , coagulase negative staphylococci, enterococci,  S. epidermidis, S. pneumoniae , and  Viridans Streptococci.    
     
     
         41 . The method of  claim 27 , wherein the composition is a gel.