Antimicrobial compounds and compositions, and uses thereof

Abstract

A method of enhancing the growth of an animal is provided. The method includes causing the animal to ingest or absorb an effective amount of one or more Fe III complex compounds, including but not limited to Fe III complexes comprising ligands bound to the iron centre selected from amino acids or α-hydroxy acids, o-hydroxy benzoic acids or pyridine-2-carboxylic acids, such as ferric quinate, ferric tyrosine, ferric DOPA and ferric phenylalanine. Compounds which are structural and/or functional variants, derivatives and/or analogs of the foregoing compounds, as further described herein are also disclosed. Methods for inhibiting, reducing, or preventing biofilm formation or buildup on a surface; the treatment of, inhibition of growth of, and inhibition of colonization by, bacteria, both in biological and non-biological environments; disinfecting surfaces, potentiating the effects of antibiotics and other anti-microbial agents, and increasing the sensitivity of bacteria and other microorganisms, to anti-microbial agents are also provided.

We claims: 
     
         1 . A method of treating a microbial infection in a human subject in need thereof, the method comprising administering to the subject an effective amount of one or more Fe III complex compounds, wherein the compound is in an effective disrupt preexist bacterial biofilm or reduce bolfilm formation, the compound having the structure of Formula A: 
       
         
           
           
               
               
           
         
       
       or a salt and/or hydrate thereof, or a functional variant thereof, wherein:
 X, X 1  and X 2  are independently NH 2 , OH, CO 2 —, CO 2 H, OR 3 , NR 3 H, NR 3 R 4 , R 3 ONO 2 , R 3 NO 2 , SH, SR 3 , and X, X 1  and X 2  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; 
 Y, Y 1  and Y 2  are independently O, NH, NH 2 , NR 3 , NR 3 R 4 , SH, OR 3 , OH, and Y, Y 1  and Y 2  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; 
 Z, Z 1  and Z 2  are independently O, S, NH, NR 3 , and Z, Z 1  and Z 2  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; 
 R, R′, R 1 , R 1′ , R 2 , and R 2′  are independently H, CH 3 , CH 2 SH, CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 C 6 H 5 , CH 2 C 3 H 3 N 2 , CH(CH 3 )CH 2 CH 3 , (CH 2 ) 4 NH 2 , CH 2 CH(CH 3 ) 2 , CH 2 CH 2 SCH 3 , CH 2 CONH 2 , (CH 2 ) 4 NHCOC 4 H 5 NCH 3 , CH 2 CH 2 CH 2 , CH 2 CH 2 CONH 2 , (CH 2 ) 3 NHC(NH)NH 2 , CH 2 OH, CH(OH)CH 3 , CH 2 SeH, CH(CH 3 ) 2 , CH 2 C 8 H 6 N, CH 2 C 6 H 4 OH and R, R′, R 1 , R 1′ , R 2 , and R 2′  may all be the same or they may all be different, or, alternatively, up to five may be the same and one or more may be different; or 
 
       any relevant pair of R and R′, R 1  and R 1′ , and R 2  and R 2′  (i.e. when they are bound to the same carbon atom) are linked to form a substituted or unsubstituted cycloalkyl ring group;
 R 3  and R 4  are independently be alkyl, alkenyl, alkynyl, phenyl, aryl, halo- and hydroxy-substituted radicals, hydroxyl radicals, nitrogen-substituted radicals, oxygen-substituted radicals, or hydrogen, and R 3  and R 4  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; and 
 
       preferably the bonds between the Fe and X, X 1  and X 2  and between the Fe and Y, Y 1  and Y 2  are ionic. 
     
     
         2 . The method of  claim 1 , wherein one, two or all three of the ligands bound to the iron center are a-hydroxy acids. 
     
     
         3 . The method of  claim 1 , wherein the microbial infection is caused by positive bacteria, or gram negative bacteria. 
     
     
         4 . The method of  claim 3 , wherein the infection is caused by bacteria selected from the group consisting of  S. epidermidis, E. faecalis, E. coli, S. aureus, H. pylori, Campylobacter , Enteropathogenic  Escherichia coli  (EPEC), Uropathogenic  Escherichia coli  (UPEC), and  Pseudomonas  or combinations thereof and/or optionally wherein the infection is not caused by bacteria that comprise, consist essentially of, or consist of proteobacteria class, such as any one or more of the spirilloid  Wolinella  spp.,  Helicobacter  spp., and most particularly  Campylobacter  spp. 
     
     
         5 . The method of  claim 1 , wherein the one or more compounds is administered to a subject by parenteral delivery; enteral delivery; oral delivery; topical delivery, such as in the form of an emulsion, lotion, cream, ointment, gel or foam; buccal delivery; sublabial delivery; sublingual delivery; in or on a dental product, such as in a toothpaste, a mouthwash, a dental floss, toothpicks, chewable products (including food products), a mouth shield, a dental instrument, dentures, dental retainers, dental braces including plastic braces (such as Invisalign), bristles of toothbrushes, dental prostheses and orthodontic devices, chewable non-food items, foods, or toys, such as dog bones and biscuits; dermal delivery; or transdermal delivery. 
     
     
         6 . The method of  claim 1 , wherein the infection is selected from the group consisting of impetigo, boils, abscesses, folliculitis, cellulitis, necrotizing fasciitis, pyomyositis, surgical/traumatic wound infection, and infected ulcers and burns), osteomyelitis, device-related osteoarticular infections, impetigo, secondarily infected skin lesions, meningitis, brain abscess, subdural empyema, spinal epidural abscess, arterial damage, gastritis, urinary tract infections, biliary tract infections, pyelonephritis, cystitis, sinus infections, ear infections, otitis media, otitis externa, leprosy, tuberculosis, conjunctivitis, bloodstream infections, benign prostatic hyperplasia, chronic prostatitis, lung infections including chronic lung infections of humans with cystic fibrosis, osteomyelitis, catheter infections, bloodstream infections, skin infections, acne, rosacea, dental caries, periodontitis, gingivitis, nosocomial infections, arterial damage, endocarditis, periprosthetic joint infections, open or chronic wound infections, venous stasis ulcers, diabetic ulcers, arterial leg ulcers, pressure ulcers, endocarditis, pneumonia, orthopedic prosthesis and orthopedic implant infections, peritoneal dialysis peritonitis, cirrhosis, and any other acute or chronic infection that involves or possesses a biofilm. 
     
     
         7 . The method of  claim 1 , wherein the infection is cause by bacteria selected from the group consisting of  Streptococcus pneumoniae, Campylobacter, Neisseria gonorrhoeae, Salmonella  (including drug-resistant non-typhoidal  Salmonella  and drug-resistant  Salmonella  serotype  typhi ), Methicillin-resistant  Staphylococcus aureus  (MRSA),  Shigella , Vancomycin-resistant  Enterococcus  (VRE), Vancomycin-resistant  Staphylococcus aureus  (VRSA), Erythromycin-resistant Group A  Streptococcus , Clindamycin-resistant Group B  Streptococcus , Carbapenem-resistant Enterobacteriaceae (CRE), drug-resistant tuberculosis, Extended spectrum Enterobacteriaceae (ESBL), multidrug-resistant  Acinetobacter  (including MRAB),  Clostridium difficile , Enteropathogenic  E. coli  (EPEC),  Pseudomonas aeruginosa , and Uropathogenic  E. coli  (UPEC). 
     
     
         8 . The method of  claim 1 , wherein the infection is caused by a drug-resistant strain of  E. coli.    
     
     
         9 . The method of  claim 1 , wherein the infection is a urinary tract infection. 
     
     
         10 . The method of  claim 1 , wherein the subject is hospitalized and/or is immunocompromised. 
     
     
         11 . The method of  claim 5  wherein the biofilm is produced by an  S. epidermidis, E. faecalis, E. coli, S. aureus, Campylobacter  spp.  H. pylori  and  Pseudomonas , alone, or in combination. 
     
     
         12 . The method of  claim 5 , wherein the infection is selected from the group consisting of acne 
     
     
         13 . A composition comprising an effective amount of a compound to inhibit bacterial biofilm formation in a human subject, wherein the compound is an Fe III complex having the structure of:
 Formula A:   
       
         
           
           
               
               
           
         
       
       or a salt and/or hydrate thereof, wherein: 
       X, X 1  and X 2  are independently selected from the group consisting of NH 2 , OH, CO 2 —, CO 2 H, OR 3 , NR 3 H, NR 3 R 4 , R 3 ONO 2 , R 3 NO 2 , SH, SR 3 , and X, X 1  and X 2  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; 
       Y, Y 1  and Y 2  are independently selected from the group consisting of O, NH, NH 2 , NR 3 , NR 3 R 4 , SH, OR 3 , OH, and Y, Y 1  and Y 2  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; 
       Z, Z 1  and Z 2  are independently selected from the group consisting of: O, S, NH, NR 3 , and Z, Z 1  and Z 2  may all be the same or they may all be different, or, alternatively, two may be the same and one may be different; 
       R, R′, R 1 , R 1′ , R 2 , and R 2′  are independently selected from the group consisting of H, CH 3 , CH 2 SH, CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 C 6 H 5 , CH 2 C 3 H 3 N 2 , CH(CH 3 )CH 2 CH 3 , (CH 2 ) 4 NH 2 , CH 2 CH(CH 3 ) 2 , CH 2 CH 2 SCH 3 , CH 2 CONH 2 , (CH 2 ) 4 NHCOC 4 H 5 NCH 3 , CH 2 CH 2 CH 2 , CH 2 CH 2 CONH 2 , (CH 2 ) 3 NHC(NH)NH 2 , CH 2 OH, CH(OH)CH 3 , CH 2 SeH, CH(CH 3 ) 2 , CH 2 C 8 H 6 N, CH 2 C 6 H 4 OH, and CH 2 C 6 H 3 (OH) 2 , and R, R′, R′, R 1′ , R 2 , and R 2′  may all be the same or they may all be different, or, alternatively, up to five may be the same and one or more may be different; or 
       any relevant pair of R and R′, R 1  and R 1′ , and R 2  and R 2′  are linked to form a substituted or unsubstituted cycloalkyl ring group; and
 R 3  and R 4  can independently be alkyl, alkenyl, alkynyl, phenyl, aryl, halo- and hydroxy-substituted radicals, hydroxyl radicals, nitrogen-substituted radicals, oxygen-substituted radicals, or hydrogen. 
 
     
     
         14 . The composition of  claim 13 , wherein R 3  and R 4  are independently C 1-4  alkyl, C 1-4  alkenyl, phenyl or benzyl, which latter four groups are optionally substituted by one or more halo or hydroxyl groups. 
     
     
         15 . The composition of  claim 13 , wherein one, two or all three of the ligands bound to the iron center are selected from amino acids or a-hydroxy acids. 
     
     
         16 . The composition of  claim 13 , comprising an effective amount of a compound to inhibit bacterial biofilm formation in a subject, the compound having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The composition of  claim 16 , wherein one, two or all three of the ligands bound to the iron center are a-hydroxy acids. 
     
     
         18 . The composition of  claim 13 , wherein the one or more compounds are in combination with one or more antimicrobial agents and one or more excipients, carriers and/or additives. 
     
     
         19 . The composition of  claim 13 , in a unit dosage form comprising one or more compounds of  claim 1  in an amount of up to, or at least, about 1 ng, 10 ng, 50 ng, 100 ng, 500 ng, 1 μg, 10 μg, 50 μg, 100 μg, 500 μg, 1 mg, 10 mg, 100 mg, 500 mg, 1 g, 2 g, 3 g, 4 g, or 5 g. 
     
     
         20 . The composition of  claim 12 , in the form of an emulsion, lotion, cream, ointment, wound dressing, patch, salve, gel, tablet, solution, suspension, foam, a spray, and an aerosol. 
     
     
         21 . The composition of  claim 12 , wherein R, R′, R′, R 1′ , R 2 , and R 2′  are independently selected from the group consisting of H, CH 3 , CH 2 SH, CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 C 6 H 5 , CH(CH 3 )CH 2 CH 3 , (CH 2 ) 4 NH 2 , CH 2 CH(CH 3 ) 2 , CH 2 CH 2 SCH 3 , CH 2 CONH 2 , (CH 2 ) 4 NHCOC 4 H 5 NCH 3 , CH 2 CH 2 CH 2 , CH 2 OH, CH(OH)CH 3 , CH 2 SeH, CH(CH 3 ) 2 , CH 2 C 8 H 6 N, CH 2 C 6 H 4 OH, and CH 2 C 6 H 3 (OH) 2 , and optionally, wherein the compound is not FeQ, FeTyr or FeDOPA.