CA2504448A1 - Transcription factor modulating compounds and methods of use thereof - Google Patents

Transcription factor modulating compounds and methods of use thereof Download PDF

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CA2504448A1
CA2504448A1 CA002504448A CA2504448A CA2504448A1 CA 2504448 A1 CA2504448 A1 CA 2504448A1 CA 002504448 A CA002504448 A CA 002504448A CA 2504448 A CA2504448 A CA 2504448A CA 2504448 A1 CA2504448 A1 CA 2504448A1
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substituted
unsubstituted
straight
branched alkyl
group
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CA2504448C (en
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Stuart B. Levy
Michael N. Alekshun
Brent L. Podlogar
Kwasi Ohemeng
Atul K. Verma
Tadeusz Warchol
Beena Bhatia
Todd Bowser
Mark Grier
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Paratek Pharmaceuticals Inc
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Abstract

Substituted benzoimidazole compounds useful as anti-infectives that decrease resistance, virulence, or growth of microbes are provided. Methods of making and using substituted benzoimidazole compounds, as well as pharmaceutical preparations thereof, in, e.g., reducing antibiotic resistance and inhibiting biofilms.

Claims (58)

1. A method for reducing antibiotic resistance of a microbial cell, comprising contacting said cell with a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that the antibiotic resistance of said cell is reduced.
2. A method for modulating a transcription, comprising contacting a transcription factor with a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that the transcription is modulated.
3. The method of claim 1 or 2, wherein R4, R5, and R7 are all H.
4. The method of claim 1 or 2, wherein R1 is selected from the group consisting of OH, O(CR'R")1-3H, O(CR'R")1-3OH, O(CR'R")1-3CO2H, O(CR'R")1-3CO2(CR'R")1-3H, O(CR'R")1-3(CO)NH2, O(CR'R")1-3(CNH)NH2, OCOCO2H, O(CR'R")1-3SO3H, O(CR'R")1-3OSO3H, O(CR'R")1-3PO3H, O(CR'R")1-3OPO3H, O(CR'R")1-3N[(CR'R")0-3H]2, O(CR'R")1-3(CO)(NHOH), and O(CR'R")1-3(heteroaryl);

wherein R' and R" are each independently H, a C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl group.
5. The method of claim 4, wherein each R' and R" is independently H or CH3.
6. The method of claim 4, wherein R1 is O(CR'R")1-3(heteroaryl), and wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group.
7. The method of claim 1 or 2, wherein R2 is a substituted or unsubstituted phenyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group.
8. The method of claim 3, wherein R6 is H, (CR'R")1-3H, (CR'R")1-3OH, (CR'R")1-3NH2, (NOH)(CR'R")1-3H, CO(CR'R")0-3-3NH2, CO(CR'R")1-3H, CO(CR'R")1-3OH, CO(CR'R")0-3CF3, (CR'R")0-3N[(CR'R")0-3H]2, CO(substituted or unsubstituted heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(CR'R")1-3H, CO(substituted or unsubstituted phenyl), CO2(CR'R")0-3H, CN, NO2, F, Cl, Br, or I, wherein R' and R" are each independently H, a C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl group.
9. The method of claim 8, wherein each R' and R" is independently H or CH3.
10. The method of claim 8, wherein R6 is CO(substituted or unsubstituted heteroaryl), and wherein said heteroaryl group is, a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group.
11. The method of claim 1 or 2, wherein said transcription factor is a helix-turn-helix protein.
12. The method of claim 1 or 2, wherein said transcription factor is a transcriptional activation factor.
13. The method of claims 12, wherein said transcriptional activation factor is an AraC family polypeptide.
14. The method of claim 12, wherein said transcriptional activation factor is a MarA
family polypeptide.
15. The method of claim 1 or 2, wherein said transcription factor modulating compound is a transcription factor inhibiting compound.
16. The method of claim 1 or 2, wherein said transcription factor is prokaryotic.
17. The method of claim 14, wherein said MarA family polypeptide is MarA, SoxS, or Rob.
18. The method of claim 1, wherein said microbial cell is selected from the group consisting of Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aenogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulganis, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotubenculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia bungdorferi, Vibrio cholerae, Yibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium. intracellulare, Mycobacterium leprae, Corynebacterium diplhtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, and Staphylococcus saccharolyticus.
19. The method of claim 1 or 2, wherein said compound is a compound of Table 6 or Table 7.
20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a transcription factor modulating compound, wherein said compound is of the formula (Va):

wherein R1 is OH, OCOCO2H, or a substituted straight or branched C1-C5 alkyloxy group, provided that R1 is not a 2-amino-substituted ethoxy group or a substituted or unsubstituted benzyloxy group;

Ra is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group, provided that said aryl group is not a thiazolyl or isothiazolyl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;

provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, or when R4, R5, and R7 are all H, R6 is C1, and R2 is para-methyl-phenyl, then R1 is not OCH2CO2CH2CH3;
or pharmaceutically acceptable salts thereof.
21. The pharmaceutical composition of claim 20, wherein R4, R5, and R7 are all H.
22. The pharmaceutical composition of claim 20, wherein R1 is selected from the group consisting of OH, O(CR'R")1-3H, O(CR'R")1-3OH, O(CR'R")1-3CO2H, O(CR'R")1-3CO2(CR'R")1-3H, O(CR'R")1-3(CO)NH2, O(CR'R")1_3(CNH)NH2, OCOCO2H, O(CR'R")1-3SO3H, O(CR'R")1-3OSO3H, O(CR'R")1-3PO3H, O(CR'R")1-3OPO3H, O(CR'R")1-3N[(CR'R")O-3H]2, O(CR'R")1-3(CO)(NHOH), and O(CR'R")1-3(heteroaryl);
wherein R' and R" are each independently H, a C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl group.
23. The pharmaceutical composition of claim 22, wherein each R' and R" is independently H or CH3.
24. The pharmaceutical composition of claim 22, wherein R1 is O(CR'R")1-3(heteroaryl), and wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group.
25. The pharmaceutical composition of claim 20, wherein R2 is a substituted or unsubstituted phenyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group.
26. The pharmaceutical composition of claim 20, wherein R6 is H, (CR'R")1-3H, (CR'R")1-3OH, (CR'R")1-3NH2, (NOH)(CR'R)1-3H, CO(CR'R")0-3NH2, CO(CR'R")1-3H, CO(CR'R")1-3OH, CO(CR'R")0-3CF3, (CR'R")0-3N[(CR'R")0-3H]2, CO(substituted or unsubstituted heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(CR'R")1-3H, CO(substituted or unsubstituted phenyl), CO2(CR'R")0-3H, CN, NO2, F, Cl, Br, or I, wherein R' and R" are each independently H, a C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl group.
27. The pharmaceutical composition of claim 26, wherein each R' and R" is independently H or CH3.
28. The pharmaceutical composition of claim 27, wherein R6 is CO(substituted or unsubstituted heteroaryl), wherein said heteroaryl group is a pyrrolyl, furanyl, thiophenyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl group.
29. The pharmaceutical composition of claim 20, further comprising an antibiotic.
30. A pharmaceutical composition of claim 20, wherein said effective amount is effective to treat a biofilm associated state in said subject.
31. The pharmaceutical composition of claim 30, wherein said biofilm associated state is selected from the group consisting of middle ear infections, cystic fibrosis, osteomyelitis, acne, dental cavities, endocarditis, and prostatitis.
32. The pharmaceutical composition of claim 20,wherein said compound is a compound of Table 6 or Table 7.
33. A method of inhibiting a biofilm, comprising administering a composition comprising a transcription factor modulating compound of the formula wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that said biofilm is inhibited.
34. The method of claim 33, wherein said transcription factor modulating compound is a compound of Table 6 or Table 7.
35. The method of claim 33, wherein said composition further comprises a surfactant.
36. The method of claim 35, wherein said surfactant is Sodium Dodecyl Sulfate;
Quaternary Ammonium Compounds; alkyl pyridinium iodides; Tween 80, Tween 85, Triton X 100; Brij 56; biological surfactants; Rhamnolipid, Surfactin, Visconsin, or sulfonates.
37. The method of claim 36, wherein said biofilm development is diminished by the administration of said composition.
38. A method of inhibiting the formation of a biofilm, comprising administering a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that the formation of said biofilm is inhibited.
39. A method for cleaning and disinfecting contact lenses comprising administering a composition comprising an acceptable carrier and a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that said contact lenses are cleaned and disinfected.
40. A method of treating medical indwelling devices comprising administering a composition comprising a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that said medical indwelling devices are treated.
41. The method of claim 40, wherein said device is selected from the group consisting of catheters, orthopedic devices and implants.
42. A method for treating or preventing a biofilm associated state in a subject, comprising administering to said subject an effective amount of a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R1 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;
provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that said biofilm associated state in said subject is treated.
43. The method of claim 42, wherein said biofilm associated state is selected from the group consisting of middle ear infections, cystic fibrosis, osteomyelitis, acne, dental cavities, endocarditis, and prostatitis.
44. The method of claim 42, further comprising administering a pharmaceutically acceptable carrier.
45. The method of claim 42, wherein said subject is a mammal.
46. The method of claim 42, wherein said mammal is a human.
47. The method of claim 42, wherein said subject is immunocompromised.
48. A method for preventing a bacterial associated state in a subject, comprising administering to said subject an effective amount of a transcription factor modulating compound of the formula (Va):
wherein R1 is OH, OCOCO2H, or a substituted or unsubstituted straight or branched C1-C5 alkyloxy group;
R2 is H, CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), or a substituted or unsubstituted aryl group; and R4, R5, R6, and R7 are independently selected from the group consisting of H, (C1-C5 substituted or unsubstituted, straight or branched alkyl), CO2(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(C1-C5 substituted or unsubstituted, straight or branched alkyl), CO(substituted or unsubstituted aryl or heteroaryl), CO(C3-C6 substituted or unsubstituted cycloalkyl), O(C1-C5 substituted or unsubstituted, straight or branched alkyl), C(NOH)(C1-C5 substituted or unsubstituted, straight or branched alkyl), substituted or unsubstituted amino, CO2H, CN, NO2, CONH2, (CO)(NHOH), and halogen;
provided that when R6 is NO2 and R2 is unsubstituted phenyl, then R1 is not O(CHCH3)(CO2)CH2CH3 or OCH2CO2H;
provided that when R6 is H or NO2, then R1 is not a phenyl-substituted alkyloxy group;

provided that when R4, R5, R6, and R7 are all H and R2 is para-methoxyphenyl, then R1 is not OH; and provided that when R4, R5, R6, and R7 are all H and R2 is unsubstituted phenyl, then R1 is not OCH2CO2CH2CH3;
such that the bacterial associated state in said subject is prevented.
49. The method of claim 48, wherein said subject is a human.
50. The method of claim 48, wherein said transcription factor modulating compound is a MarA family polypeptide inhibitor.
51. The method of claim 48, wherein said transcription factor modulating compound is a AraC family polypeptide inhibitor.
52. A method for reducing antibiotic resistance of a microbial cell, comprising contacting said cell with a transcription factor modulating compound of Table 8, such that the antibiotic resistance of said cell is reduced.
53. A method for modulating a transcription, comprising contacting a transcription factor with a transcription factor modulating compound of Table 8, such that transcription is modulated.
54. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a transcription factor modulating compound, wherein said compound is of Table 8.
55. A method of inhibiting the formation of a biofilm, comprising administering a transcription factor modulating compound of Table 8, such that a biofilm is inhibited.
56. A method for preventing a bacterial associated state in a subject, comprising administering to said subject an effective amount of a transcription factor modulating compound of Table 8. such that a bacterial associated state is prevented.
57. A method for treating or preventing a biofilm associated state in a subject, comprising administering to said subject an effective amount of a transcription factor modulating compound of Table 8, such that said biofilm associated state is treated or prevented.
58. A compound of Table 6, Table 7, or Table 8.
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