Inhibitors of cellular efflux pumps of microbes

A method for prophylactic treatment of an animal at risk for developing a microbial infection comprising administering to the animal an antimicrobial agent and an efflux pump inhibitor in an amount sufficient to reduce efflux pump activity,

• wherein said efflux pump inhibitor increases the susceptibility of said microbe to said antimicrobial agent, and
• wherein said efflux pump inhibitor has the chemical structure of structure 1 below:
• 27
• Wherein,
• R1=H, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, or when X is C and the nitrogen atom to which R. is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R, is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2- and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2 H, CHO, COOR3, or CONHR13, where R13=H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH(R14) OC(═O)R15, (CH2)nCH(R,4) C(═O)OR,5 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 28
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B=N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5=H, Cl 5 alkyl, amino, alkylamino, or acylamino;
• R6=H, C1-6 alkyl, halo ,amino, or hydroxy;
• R7 ═OH, halo or NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R10 taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR11, or NH(CH2)nNR9 R10;
• or R7=
• 29
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W═NH or when Z═N, W is absent;
• or
• 30
• where n=0,1,or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H11O6, SO3H, or PO3H2,
• R11=H, C1-6 alkyl, C3-6 cycloalkyl, or heterocyclic group,
• X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCRF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen, oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

A method of enhancing the antimicrobial activity of an antimicrobial agent against a microbe, comprising contacting said microbe with said antimicrobial agent and an efflux pump inhibitor in an amount effective to inhibit an efflux pump in said microbe,

• wherein said efflux pump inhibitor has the chemical structure of structure 1 below:
• 33
• wherein,
• R1 =H, C1-6 alkyl, C3-6 cycloalkyl, or opfionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, or when X is C and the nitrogen atom to which R1 is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R1 is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2- and CH2CH2CH2Y- where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2=H, CHO, COOR3, or CONHR13, where R13=H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypepfidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH(R,4) OC(═O)R15, (CH2)nCH(R14) C(═O)OR15 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 34
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5=H, C15 alkyl, amino, alkylamino, or acylamino;
• R=H, C1-6 alkyl, halo ,amino, or hydroxy;
• R7 ═OH, halo or
• NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R10 taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR1 I, or NH(CH2)nNR9 R1o;
• or R7=
• 35
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W=NH or when Z═N, W is absent;
• or
• 36
• where n=0,1,or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H11O6, SO3H, or PO3H2,
• R1I=H, C1-6 alkyl, C3-6 cycloalkyl, or heterocyclic group,
• X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCHF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen , oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

The method of suppressing growth of a microbe expressing an efflux pump, comprising contacting said microbe with an efflux pump inhibitor in the presence of a concentration of antimicrobial agent below the MIC of said microbe, whrein said efflux pump inhibitor has the chemical structure of structure 1 below:

• 39
• wherein,
• R1=H, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl,
• arylS(O)talkyl, where t=0,1 or 2, or when X is C and the nitrogen atom to which R, is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably, R1 is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2— and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C64 alkyl group;
• R2=H, CHO, COOR3, or CONHR13, where R13 H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2,
• (CH2)nCH(R14) OC(═O)R15, (CH2)nCH(R14) C(═O)OR15 wherein n=0-6, R4=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 40
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4═H R4=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5═H, C1-5 alkyl, amino, alkylamino, or acylamino;
• R6═H, C1-6 alkyl, halo, amino, or hydroxy;
• R7═OH, halo or
• NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R1O taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR11, or NH(CH2)nNR9 R10;
• or R7=
• 41
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W═NH or when Z═N, W is absent;
• or
• 42
• where n═0,1, or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H,1O6, SO3H, or PO3H2,
• R11=H, C1 alkyl, C3-6 cycloalkyl, or heterocyclic group,
• X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCHF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen, oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

An efflux inhibitor compound, wherein said compound has the chemical structure 1 below:

• 45
• wherein,
• R1=H, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, or when X is C and the nitrogen atom to which R1 is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R1 is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2- and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2 H, CHO, COOR3, or CONHR13, where R13=H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH(R14) OC(═O)R15, (CH2)nCH(R14) C(═O)OR,5 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 46
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5=H, C15 alkyl, amino, alkylamino, or acylamino;
• R6=H, C1-6 alkyl, halo, amino, or hydroxy;
• R7=OH, halo or NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R10 taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR, or NH(CH2)nNR9 R10;
• or R7=
• 47
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W═NH or when Z═N, W is absent;
• or
• 48
• where n=0,1,or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H11O6, SO3H, or PO3H2,
• R1,=H, C1 alkyl, C3-6 cycloalkyl, or heterocyclic group,
• X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCHF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen , oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

An efflux pump inhibitor of the Mef pump wherein said efflux pump inhibitor has the Structure 1 below

• 51
• wherein,
• R1=H, C16 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, 20 or when X is C and the nitrogen atom to which R1 is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R. is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2— and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2=H, CHO, COOR3, or CONHR13, where R13=H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH(R,4) OC(═O)R15, (CH2)nCH(R14) C(═O)OR,5 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 52
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5=H, C15 alkyl, amino, alkylamino, or acylamino;
• R6=H, C1-6 alkyl, halo ,amino, or hydroxy;
• R7 ═OH, halo or NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R10 taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR11, or NH(CH2)nNR9 R10 ;
• or R7=
• 53
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W═NH or when Z═N, W is absent;
• or
• 54
• where n=0,1,or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H,1O6, SO3H, or PO3H2,
• R11=H, C1-6 alkyl, C3-6 cycloalkyl, or heterocyclic group, X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCHF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen , oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

An efflux pump inhibitor of the NorA, Bmr, PmrA, QacA and/or QacB pump/s wherein said efflux pump inhibitor has the Structure 1 below

• 55
• wherein,
• R1 =H, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O),alkyl, where t=0,1 or 2, or when X is C and the nitrogen atom to which R1 is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R1 is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2y—, CH2CH2CH2CH2- and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2=H, CHO, COOR3, or CONR13, where R13=H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH(R14) OC(═O)R15, (CH2)nCH(R14) C(═O)OR15 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 56
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (=0)nor thio (═S);
• R5=H, C15 alkyl, amino, alkylamino, or acylamino;
• R6=H, C1-6 alkyl, halo ,amino, or hydroxy;
• R7=OH, halo or NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R10 taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substituted;
• or R7=NHOA, NHCOOR11, or NH(CH2)nNR9 R10;
• or R7=
• 57
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W═NH or when Z═N, W is absent;
• or
• 58
• where n=0, 1,or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H11O6, SO3H, or PO3H2,
• R11=H, C1-6 alkyl, C3-6 cycloalkyl, or heterocyclic group,
• X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCHF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen , oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

An efflux pump inhibitor of the MexAB-OprM, MexCD-OprJ, MexEF-OprM, MexXY-OprM, AcrAB-ToIC, AcrEF, MarA, SoxS and/or Tet pump/s, wherein said efflux pump inhibitor has the Structure 1 below

• 59
• wherein,
• R1 =H, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t═O,1 or 2, or when X is C and the nitrogen atom to which R, is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R1 is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2— and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2 H, CHO, COOR3, or CONHR13, where R,3=H or the NHR13 of CONEIR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH(R,4) OC(═O)R15, (CH2)nCH(R14) C(═O)OR15 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 60
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5 =H, C1-5 alkyl, amino, alkylamino, or acylamino;
• R6 =H, C1-6 alkyl, halo ,amino, or hydroxy;
• R7 =OH, halo or NR9 R10 wherein R9 and R10 are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R10 is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R10 through an atom of the heterocycle other than the heterocyclic atom or R9 and R1 o taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR11, or NH(CH2)nNR9 R10 ;
• or R7=
• 61
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W═NH or when Z═N, W is absent;
• or
• 62
• where n=0,1, or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C1-6 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H11O6, SO3H, or PO3H2,
• R11=H, C1-6 alkyl, C36 cycloalkyl, or heterocyclic group,
• X=CH,I C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCHF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen , oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs.

A pharmaceutical composition effective for treatment of an infection of an animal by a microbe, comprising an efflux pump inhibitor and a pharmaceutically acceptable carrier, wherein said efflux pump inhibitor has the chemical structure of structure 1 below:

• 63
• wherein,
• R1=H, C1-6 alkyl, C3-6 cycloalkyl, or optionally substituted aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, or when X is C and the nitrogen atom to which R1 is linked forms an optionally substituted 4-, 5-, 6- or 7-membered ring with X of the adjacent ring, the ring optionally containing one or more hetero atoms selected from nitrogen , oxygen or sulfur atoms said heteroatom(s) represented by Y, preferably R1 is —CH2CH2—, CH2Y—, CH2CH2CH2—, CH2CH2Y—, CH2CH2CH2CH2- and CH2CH2CH2Y— where Y represents NH, O, or S. If the ring is substituted, the substituent is C1-6 alkyl group;
• R2 H, CHO, COOR3, or CONHR13, where R13=H or the NHR13 of CONHR13 is the residue of one of the 20 naturally occurring amino acids:
• alanine, arginine, asparagines, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or the optically active isomers thereof or the racemic mixtures thereof, or combinations of these amino acids to give dipeptidyl, tripeptidyl or polypeptidyl residues;
• R3=H, C1-6 alkyl, C3-6 cycloalkyl, aryl, aralkyl, arylaminoalkyl, aryloxyalkyl, arylS(O)talkyl, where t=0,1 or 2, (CH2)nCH1(R4) OC(═O)R,5, (CH2)nCH(R,4) C(═O)OR15 wherein n=0-6, R14=H or CH3;
• and R15=C2H5 or C(CH3)3;
• or R3 is
• 64
• wherein B═CH or N, and when B═CH, Z═NH or NCH3, and when B═N, Z═CH, O, NH S or NCH3;
• p=0-2;
• q=0-2,
• R4=H, R4a=H, or R4 and R4a taken together are oxo (═O), or thio (═S);
• R5=H, C1 5 alkyl, amino, alkylamino, or acylamino;
• R6=H, C1-6 alkyl, halo ,amino, or hydroxy;
• R7 ═OH, halo or NR9 R1 ( wherein R9 and R1O are the same or different and represent H, C1-6 alkyl or (CH2)nOA,
• or R9 is H and R1o is a 4-membered, 5-membered, 6-membered, or 7-membered carbocyclic, mono or bicyclic ring or mono or bicyclic heterocyclic ring linked to the nitrogen of NR9 R1o through an atom of the heterocycle other than the heterocyclic atom or R9 and R10 taken together with the nitrogen atom to which they are attached form part of a heterocycle which heterocycle is monocyclic, bicyclic, and said carbocycle and heterocycle is optionally substitued;
• or R7=NHOA, NHCOOR11, or NH(CH2)nNR9 R10;
• or R7=
• 65
• where n=1,2 or 3, Z═CH or N, and when Z═CH, W=NH or (o)n when Z═N, W is absent;
• or
• 66
• where n=0,1,or 2
• wherein the R7 moiety is linked either to 2 core molecules of the Formula I to form a bis compound or the R7 moiety has one of its link bonds linked to the core formula of Formula I and the second of its link bonds is linked to an optionally substituted phenyl carboxylic acid or ester moiety thereof,
• A=H, C1-6 alkyl, glycosyl, aralkyl, C16 alkanoyl or aminoalkanoyl wherein the aminoalkanoyl group may be an aminoacid residue derived from one of the one of the 20 naturally occurring amino acids or the optically active isomers thereof, or the racemic mixtures thereof wherein the amino residue is derived from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine;
• or.
• A is C6H11O6, SO3H, or PO3H2,
• R11=H, C1-6 alkyl, C3-6 cycloalkyl, or heterocyclic group,
• X=CH, C—F, C—Cl, C—CH3, C—CF3, C—OCH3, C—OCIF2, C—OCF3, N or when X is equal to C it forms together with the nitrogen atom of the adjacent ring an optionally substituted 5-membered ring, 6-membered ring, 7-membered ring, containing carbon atoms and optionally Y atoms representing one or more nitrogen , oxygen or sulfur atoms;
• if the ring is substituted, the substituent is C1-6 alkyl group;
• and their pharmaceutically acceptable salts, hydrates, polymorphs and pseudopolymorphs;