Antimicrobial peptides derived from cap18

Abstract

The present invention relates to a group of peptidic compounds which have antimicrobial activity. The compounds also have affinity for toxins and especially for bacterial toxins, such as lipopolysaccharide or lipoteichoic acid. The compounds can be used to manufacture medicaments useful for the treatment of bacterial or fungal infections. The medicaments may be administered systemically or locally.

1 . A method to inhibit the formation of, or disrupt or degrade biofilms in a mammal, which method comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (1) that comprises a core amino acid sequence: X 1 KEFX 2 RIVX 3 RIKX 4 FLRX 5 LVX 6  (SEQ ID NO;1), wherein
 X 1  represents an N-terminal part;   X 2  is K or E;   X 3  is Q or E;   X 4  is D or R;   X 5  is N or E;   X 6  represents a C-terminal part;   wherein one or more of the amino acids of the core amino acid sequence is optionally derivatized, and wherein   (a) the N-terminal part is acetylated, and/or   (b) the C-terminal part is amidated, and/or   (c) the core amino acid sequence is different from   
       
         
           
                 
                 
                 
               
                     
                   KEFKRIVQRIKDFLRNLV. 
                   (SEQ ID NO: 2) 
                 
             
                
               
            
           
         
       
     
     
         2 . The method according to  claim 1 , wherein said biofilms are caused by sessile, biofilm-forming microorganisms. 
     
     
         3 . The method according to  claim 1 , wherein the biofilms are associated with periodontitis, native valve endocarditis, cystic fibrosis, chronic bacterial prostatitis, bronchitis, pneumonia, sinusitis, dental caries, chronic tonsillitis, endocarditis, necrotizing fasciitis, musculoskeletal infection, osteomyelitis, biliary tract infection, or infectious kidney stones. 
     
     
         4 . The method according to  claim 1 , wherein the biofilms are associated with an infection of the liver, the spleen, the periodontium, an eye, a kidney, the skin, the vagina, the urethra, or the heart. 
     
     
         5 . The method according to  claim 1 , wherein the compound is present in a fluid at a concentration of at least 0.001 μM. 
     
     
         6 . The method according to  claim 5 , wherein the compound is present in the fluid at a concentration in the range from 0.1 to 100 μM. 
     
     
         7 . The method according to  claim 1 , wherein the compound is formulated and processed for parenteral injection, instillation or irrigation. 
     
     
         8 . The method according to  claim 1 , wherein the compound is formulated substantially free of preservatives. 
     
     
         9 . The method according to  claim 1 , wherein the N-terminal part X 1  comprises the amino acids I and/or G. 
     
     
         10 . The method according to  claim 1 , wherein the C-terminal part X 6  comprises a sequence of at least 4 amino acids or amino acid derivatives. 
     
     
         11 . The method of  claim 1 , wherein the C-terminal part X 6  comprises PRTE or RPLR, wherein one or more of the amino acids of said C-terminal part X 6  is optionally derivatized. 
     
     
         12 . The method of  claim 1 , wherein the compound comprises a peptide with a sequence of 24 amino acids or derivatives thereof, said sequence being selected from
 IGKEFKRIVQRIKDFLRNLVPRTE (SEQ ID NO:3) and   IGKEFKRIVERIKRFLRELVRPLR (SEQ ID NO:4), and wherein one or more of the amino acids is optionally derivatized.   
     
     
         13 . The method of  claim 12 , wherein the N-terminus is acetylated and the C-terminus is amidated. 
     
     
         14 . A method to prevent or manage an infection resulting from insertion or implantation of a medical device in the body of a mammal for a diagnostic or therapeutic purpose
 which method comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (1) that comprises a core amino acid sequence: X 1 KEFX 2 RIVX 3 RIKX 4 FLRX 5 LVX 6 (SEQ ID NO:1), wherein   X 1  represents an N-terminal part;   X 2  is K or E;   X 3  is Q or E;   X 4  is D or R;   X 5  is N or E;   X 6  represents a C-terminal part;   wherein one or more of the amino acids of the core amino acid sequence is optionally derivatized, and wherein   (a) the N-terminal part is acetylated, and/or   (b) the C-terminal part is amidated, and/or   (c) the core amino acid sequence is different from   
       
         
           
                 
                 
                 
               
                     
                   KEFKRIVQRIKDFLRNLV. 
                   (SEQ ID NO: 2) 
                 
             
                
               
            
           
         
       
     
     
         15 . The method according to  claim 14 , wherein the medical device is a contact lens, a heart valve, a venous catheter, a urinary catheter, a speech button, a tympanostomy tube, an intrauterine device, a suture, a vascular graft, a vascular shunt, a peritoneal dialysis deice, a penile prosthesis, an orthopaedic prosthesis, or an artificial bone. 
     
     
         16 . The method according to  claim 14 , wherein the compound is present in a fluid at a concentration of at least 0.001 μM. 
     
     
         17 . The method according to  claim 16 , wherein the compound is present in the fluid at a concentration in the range from 0.1 to 100 μM. 
     
     
         18 . The method according to  claim 14 , which compound is formulated and processed for parenteral injection, instillation or irrigation. 
     
     
         19 . The method according to  claim 14 , wherein the compound is formulated substantially free of preservatives. 
     
     
         20 . The method according to  claim 14 , wherein the N-terminal part X 1  comprises the amino acids I and/or G. 
     
     
         21 . The method according to  claim 14 , wherein the C-terminal part X 6  comprises a sequence of at least 4 amino acids or amino acid derivatives. 
     
     
         22 . The method of  claim 14 , wherein the C-terminal part X 6  comprises PRTE or RPLR, wherein one or more of the amino acids of said C-terminal part X 6  is optionally derivatized. 
     
     
         23 . The method of  claim 1 , wherein the compound comprises a peptide with a sequence of 24 amino acids or derivatives thereof, said sequence being selected from
 IGKEFKRIVQRIKDFLRNLVPRTE (SEQ ID NO:3) and   IGKEFKRIVERIKRFLRELVRPLR (SEQ ID NO:4), and wherein one or more of the amino acids is optionally derivatized.   
     
     
         24 . The method of  claim 23 , wherein the N-terminus is acetylated and the C-terminus is amidated.