ZINC IONOPHORES AND USES THEREOF

1 - 29 . (canceled)

30 . A method of treating a bacterial infection in a subject comprising administering to a subject in need thereof an effective amount of a pharmaceutically acceptable zinc ionophore or a pharmaceutically acceptable derivative thereof, separately, concurrently or sequentially, and in any order, with administration of a therapeutically effective amount of an antibiotic or a pharmaceutically acceptable derivative thereof.

31 . The method according to claim 30 , wherein the zinc ionophore or a pharmaceutically acceptable derivative thereof, is in combination with an effective amount of a pharmaceutically acceptable zinc(II) salt or pharmaceutically acceptable solvate thereof, and wherein the antibiotic is not an aminoglycoside antibiotic.

32 . The method according to claim 30 , wherein the zinc ionophore is an 8-hydroxyquinoline derivative of Formula (I) as defined in WO2004/007461.

33 . The method according to claim 30 , wherein the zinc ionophore is a compound of Formula I:

wherein R 1a and R 1b are independently H, halogen, OR 2a , SR 2a , CF 3 , C 1-4 alkyl, or NR 2a R 2b ; R 2a and R 2b are independently H, or optionally substituted C 1-4 alkyl;

or a pharmaceutically acceptable derivative thereof;

or a compound of Formula II:

wherein:

R 3 and R 5 are independently H; optionally substituted C 1-6 alkyl; optionally substituted C 2-6 alkenyl; optionally substituted C 2-6 alkynyl; optionally substituted C 3-6 cycloalkyl; optionally substituted aryl; optionally substituted heterocyclyl; CN; OR 6 , SR 6 , COR 6 , CSR 6 , HCNOR 6 or HCNNR 6 in which R 6 is H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; NR 8 R 9 or SO 2 NR 8 R 9 in which R 8 and R 9 are independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl; CONR 9 R 10 in which R 9 is as defined above and R 10 is optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; CH 2 CONR 8 R 9 in which R 8 and R 9 are as defined above; and (CH 2 ) n NR 9 R 11 in which R 9 is as defined above and R 11 is selected from optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and SO 2 R 12 in which R 12 is optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1 to 6;

R 4a and R 4b are independently H, optionally substituted C 1-4 alkyl or halogen;

or a pharmaceutically acceptable derivative thereof.

34 . The method according to claim 30 , wherein the zinc ionophore is 5,7-dichloro-2-[(dimethylamino)methyl]-8-quinolinol (PBT2):

or a pharmaceutically acceptable derivative thereof.

35 . The method according to claim 30 , wherein the antibiotic is a carbapenem, a cephalosporin, a glycopeptide, a lincosamide, a macrolide, a monobactam, a nitrofuran, an oxazolidinone, a penicillin, a polypeptide, a quinolone, a sulphonamide, or a tetracycline; or chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, thiamphenicol, tigecycline, tinidazole, or trimethoprim, or a pharmaceutically acceptable derivative of any one thereof.

36 . The method according to claim 30 , wherein the antibiotic is a polypeptide antibiotic or a pharmaceutically acceptable salt thereof.

37 . The method according to claim 36 , wherein the polypeptide antibiotic is a polymyxin.

38 . The method according to claim 30 , wherein the antibiotic is colistin, polymyxin B, tetracycline, tigecycline, doxycycline, oxacillin, erythromycin, ampicillin, vancomycin, penicillin, or chloramphenicol, or a pharmaceutically acceptable derivative of any one thereof.

39 . The method according to claim 30 , wherein the bacterial infection involves a Gram positive bacterium.

40 . The method according to claim 30 , wherein the bacterial infection involves a Gram negative bacterium.

41 . The method according to claim 30 , wherein a pathogenic bacterium involved in the bacterial infection is a Klebsiella spp, an Erythromycin-resistant Group A Streptococcus spp., methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Escherichia coli, Streptococcus pneumonia, Neisseria spp., Acinetobacter spp., and Pseudomonas spp.

42 . A method of restoring the sensitivity of a resistant pathogenic bacterium to an antibiotic or for inhibiting resistance of a pathogenic bacterium to an antibiotic comprising the steps of:

administering an effective amount of a pharmaceutically acceptable zinc ionophore or a pharmaceutically acceptable salt thereof;

administering an effective amount of an antibiotic or a pharmaceutically acceptable salt thereof; and, optionally,

administering an effective amount of a pharmaceutically acceptable zinc(II) salt or a pharmaceutically acceptable solvate thereof;

to a subject in need thereof;

wherein the steps are concurrent, sequential or separate and may performed in any order.

43 . A pharmaceutical composition comprising a pharmaceutically acceptable zinc ionophore or a pharmaceutically acceptable derivative thereof and an antibiotic or a pharmaceutically acceptable derivative thereof; and, optionally, a pharmaceutically acceptable zinc(II) salt or pharmaceutically acceptable solvate thereof; and

a pharmaceutically acceptable carrier.

44 . A method of treating a bacterial infection in a subject comprising the administration of a therapeutically effective and non-toxic amount of a pharmaceutical composition according to claim 43 .

45 . The composition according to claim 43 , wherein the zinc ionophore is a compound of Formula I:

wherein R 1a and R 1b are independently H, halogen, OR 2a , SR 2a , CF 3 , C 1-4 alkyl, or NR 2a R 2b ; R 2a and R 2b are independently H, or optionally substituted C 1-4 alkyl;

or a pharmaceutically acceptable derivative thereof;

or a compound of Formula II:

wherein:

R 3 and R 5 are independently H; optionally substituted C 1-6 alkyl; optionally substituted C 2-6 alkenyl; optionally substituted C 2-6 alkynyl; optionally substituted C 3-6 cycloalkyl; optionally substituted aryl; optionally substituted heterocyclyl; CN; OR 6 , SR 6 , COR 6 , CSR 6 , HCNOR 6 or HCNNR 6 in which R 6 is H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; NR 8 R 9 or SO 2 NR 8 R 9 in which R 8 and R 9 are independently selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl and optionally substituted heterocyclyl; CONR 9 R 10 in which R 9 is as defined above and R 10 is optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl; CH 2 CONR 8 R 9 in which R 8 and R 9 are as defined above; and (CH 2 ) n NR 9 R 11 in which R 9 is as defined above and R 11 is selected from optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and SO 2 R 12 in which R 12 is optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heterocyclyl, and n is 1 to 6;

R 4a and R 4b are independently H, optionally substituted C 1-4 alkyl or halogen;

or a pharmaceutically acceptable derivative thereof.

46 . The composition according to claim 43 , wherein the zinc ionophore is

5,7-dichloro-2-[(dimethylamino)methyl]-8-quinolinol (PBT2):

or a pharmaceutically acceptable derivative of either thereof.

47 . The composition according to claim 43 , wherein the antibiotic is a carbapenem, a cephalosporin, a glycopeptide, a lincosamide, a macrolide, a monobactam, a nitrofuran, an oxazolidinone, a penicillin, a polypeptide, a quinolone, a sulphonamide, or a tetracycline; or chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, thiamphenicol, tigecycline, tinidazole, or trimethoprim, or a pharmaceutically acceptable derivative of any one thereof.

48 . The composition according to claim 43 wherein the antibiotic is colistin, polymyxin B, tetracycline, tigecycline, doxycycline, oxacillin, erythromycin, ampicillin, vancomycin, penicillin, or chloramphenicol, or a pharmaceutically acceptable derivative of any one thereof.

49 . The composition according to claim 43 wherein the antibiotic is a polypeptide antibiotic or a pharmaceutically acceptable derivative thereof.