Class IIa HDAC inhibitors for the treatment of infection
In some aspects, methods for treating a bacterial infection in a mammalian subject are provided. In some embodiments, a class IIa HDAC inhibitor such as, e.g., a HDAC4 inhibitor, may be used to treat a bacterial infection such as, e.g., anthrax, pertussis, tuberculosis, or cholera.
1. A method of inhibiting a bacterial toxin that increases or stimulates production of cAMP in a subject comprising administering an effective dose of a class Ila Histone deacetylase (HDAC) inhibitor to the subject, wherein the class IIa HDAC inhibitor is valproic acid (sodium 2-propylpentanoate), Trichostatin A ((2E,4E,6R)-7-(4-(Dimethylamino)phenyl)-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide), LMK235 (N-[[6-(Hydroxyamino)-6-oxohexyl]oxy]-3,5-dimethylbenzamide), MC1568 (3-[5-(3-(3-Fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide) or SAHA (N-Hydroxy-N′-phenyloctanediamide); and wherein the inhibitor inhibits HDAC4.
2. The method of claim 1 , wherein the bacterial toxin is secreted by or results from infection by anthrax ( Bacillus anthracis ), tuberculosis ( Mycobacterium tuberculosis ), pertussis ( Bordetella pertussis ), or cholera ( Vibrio cholerae ).
3. The method of claim 1 , wherein the class IIa HDAC inhibitor is MC1568 (3-[5-(3-(3-Fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide).
4. The method of claim 1 , wherein the class IIa HDAC inhibitor is LMK235 (N-[[6-(Hydroxyamino)-6-oxohexyl]oxy]-3,5-dimethylbenzamide), MC1568 (3-[5-(3-(3-Fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide), or Trichostatin A ((2E,4E,6R)-7-(4-(Dimethylamino)phenyl)-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide).
5. The method of claim 1 , wherein the class IIa HDAC inhibitor is comprised in a pharmaceutical preparation comprising an excipient.
6. The method of claim 5 , wherein the pharmaceutical preparation is formulated for oral, intravenous, or parenteral administration.
7. The method of claim 1 , wherein the method further comprises administering a second antibacterial therapy to the subject, wherein second antibacterial therapy comprises administering an antibiotic to the subject.
8. The method of claim 7 , wherein the antibiotic is ciprofloxacin, doxycycline, erythromycin, vancomycin, penicillin, streptomycin, bedaquiline, delamanid, erythromycin, azithromycin, or trimethoprim-sulfamethoxazole (TMP-SMZ).
9. The method of claim 1 , wherein the subject is a human.
10. The method of claim 2 , wherein the bacterial toxin is secreted by or results from infection by pertussis ( Bordetella pertussis ).
11. The method of claim 2 , wherein the bacterial toxin is secreted by or results from infection by tuberculosis ( Mycobacterium tuberculosis ).
12. The method of claim 1 , wherein the inhibitor is valproic acid (sodium 2-propylpentanoate).
13. The method of claim 1 , wherein the inhibitor is SAHA (N-Hydroxy N′ phenyloctanediamide).