Antimicrobial therapy for bacterial infections
View Patent ↗The disclosure provides compounds and methods to treat bacterial pathogenesis, and demonstrates that the S. aureus pigment is a virulence factor and potential novel target for antimicrobial therapy.
1. A method for treating a bacterial infection, comprising:
(a) providing a composition comprising a compound having a Formula I or a Formula II:
wherein:
m is 0, 1, 2 or 3;
n is an integer between 1 and 10 inclusive;
each D and E are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
M 1 M 2 , and M 3 are each independently selected from the group consisting of metals, ammonium and esters thereof;
R 1 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 1 and R 2 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 2 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 2 and R 1 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 2 and R 3 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 3 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 3 and R 2 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 3 and R 4 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 4 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 4 and R 3 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
L 1 is —S—, —SO—, —SO 2 —, —O—, —N(R 19 )—, or —C(R 20 )(R 21 )—; wherein R 19 , R 20 and R 21 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
wherein:
x is 0, 1 , 2, or 3;
y is an integer between 1 and 10 inclusive;
each G and J are independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
M 4 , M 5 , and M 6 are each independently selected from the group consisting of metals, ammonium and esters thereof;
R 10 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 10 and R 11 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 11 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 11 and R 10 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 11 and R 12 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 12 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 12 and R 11 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 12 and R 13 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 13 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 13 and R 12 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 14 , R 15 , R 16 , R 17 , and R 18 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
L 2 is —S—, —SO—, —SO 2 —, —O—, —N(R 22 )—, or —C(R 23 )(R 24 )—; wherein R 22 , R 23 and R 24 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo; and
(b) contacting the composition with the bacterial microbe, thereby treating a bacterial infection, wherein the bacterial microbe expresses a carotenoid and wherein the compound inhibits the production of the carotenoid rendering the bacterial microbe more susceptible to oxidative damage.
2. The method of claim 1 , wherein:
m is zero or one;
n is an integer between 1 and 5, inclusive;
each D and E are independently selected from H, alkyl, substituted alkyl and halo;
R 1 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 1 and R 2 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 2 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 2 and R 1 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring, or R 2 and R 3 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 3 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 3 and R 2 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring, or R 3 and R 4 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 4 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 4 and R 3 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo;
R 19 , R 20 and R 21 are each independently selected from the group consisting of: H, alkyl, and substituted alkyl;
M 1 , M 2 , and M 3 are each independently alkali metals;
x is zero or one;
y is an integer between 1 and 5, inclusive;
each G and J are independently selected from H, alkyl, substituted alkyl and halo;
R 10 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 10 and R 11 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 11 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 11 and R 10 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring, or R 11 and R 12 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 12 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 12 and R 11 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring, or R 12 and R 13 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 13 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo or R 13 and R 12 , together with the carbons to which they are bound, can be joined to form a furan, substituted furan, pyran, substituted pyran, pyrrole, substituted pyrrole, pyridine, substituted pyridine, aromatic, or substituted aromatic, cyclopentyl, substituted cyclopentyl, cyclohexyl, or substituted cyclohexyl ring;
R 14 , R 15 , R 16 , R 17 , and R 18 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, and halo;
R 22 , R 23 , and R 24 are each independently selected from the group consisting of: H, alkyl, and substituted alkyl;
M 4 , M 5 , and M 6 are each independently alkali metals.
3. The method of claim 1 , wherein:
m is one;
n is three;
each D and E are H;
R 1 is H, F, or benzyl;
R 2 is H, F or CF 3 ;
R 3 is H, F, Cl, CF 3 , t-butyl, n-propyl, or benzyl;
R 4 is H or F;
R 5 , R 6 , R 7 and R 9 are each H;
R 8 is H or F;
M 1 , M 2 , and M 3 are each potassium;
L 1 is —O—, —NH—or CH 2 ;
x is zero or one;
y is three;
each G and J are H;
R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 are each H;
R 12 is H or CH 3
M 4 , M 5 , and M 6 are each potassium;
L 2 is —O—.
4. The method of claim 1 , wherein the compound is selected from the group consisting of:
5. The method of claim 1 , wherein the compound inhibits crtM (dehydrosqualene synthase) or crtN (dehydrosqualene desaturase).
6. The method of claim 1 wherein the carotenoid is a staphyloxanthin.
7. The method of claim 1 , wherein the compound is of Formula III
8. The method of claim 1 , wherein the compound further comprises a pharmaceutically acceptable carrier.
9. The method of claim 1 , wherein the compound is formulated or manufactured as a tablet, a pill, a capsule, a coating, a microsphere, liposome, a wipe, a lotion, a cream, a gel, an ointment or a spray; or formulated for delivery intramuscularly, intravenously, intraperitoneally, subcutaneously, by inhalation or transdermally.
10. The method of claim 1 , wherein the bacterial infection is a Staphylococcus infection, or a bacterial infection caused by a Staphylococcus sp. or a Staphylococcus aureus.
11. The method of claim 1 , wherein the contacting of the bacterial microbe with the compound is in vivo or in vitro.
12. A method of inhibiting the growth of a bacterial microbe, comprising
(a) contacting the bacterial microbe in vivo or in vitro with a compound, wherein the compound has a Formula I or a Formula II:
wherein:
m is 0, 1, 2 or 3;
n is an integer between 1 and 10 inclusive;
each D and E are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
M 1 M 2 , and M 3 are each independently selected from the group consisting of metals, ammonium and esters thereof;
R 1 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 1 and R 2 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 2 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 2 and R 1 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 2 and R 3 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 3 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 3 and R 2 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 3 and R 4 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 4 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 4 and R 3 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
L 1 is —S—, —SO—, —SO 2 —, —O—, —N(R 19 )—, or —C(R 20 )(R 21 )—; wherein R 19 , R 20 and R 21 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
wherein:
x is 0 , 1 , 2 , or 3;
y is an integer between 1 and 10 inclusive;
each G and J are independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
M 4 , M 5 , and M 6 are each independently selected from the group consisting of metals, ammonium and esters thereof;
R 10 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 10 and R 11 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 11 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 11 and R 10 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 11 and R 12 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 12 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 12 and R 11 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring, or R 12 and R 13 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 13 is selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo, or R 13 and R 12 , together with the carbons to which they are bound, can be joined to form a 4 to 7 membered ring or a substituted 4 to 7 membered ring;
R 14 , R 15 , R 16 , R 17 , and R 18 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo;
L 2 is —S—, —SO—, —SO 2 —, —O—, —N(R 22 )—, or —C(R 23 )(R 24 )—; wherein R 22 , R 23 and R 24 are each independently selected from the group consisting of: H, aryl, substituted aryl, alkyl, substituted alkyl, carboxyl, aminocarbonyl, alkylsulfonylaminocarboxyl, alkoxycarbonyl, and halo.
13. The method of claim 12 , wherein the contacting in vivo is to treat a Staphylococcus infection, or Staphylococcus aureus infection.
14. The method of claim 13 , wherein
(a) the contacting is on a surface of a bacterial microbe comprising a carotenoid
(b) the bacteria is gram positive,
(c) bacteria is Staphylococcus aureus or S. epidermidis;
(e) the bacteria is gram negative,
(e) the bacteria is selected from the group consisting of E. coli, P. aeruginosa , and S. typhimurium.