Type III secretion inhibitors, analogs and uses thereof
The invention, in some aspects, relates to compounds and compositions useful for inhibiting Type III secretion systems in pathogenic bacteria, such as Yersinia Pestis . In some aspects, the invention relates to methods for discovering inhibitors of the Type III secretion system and uses of such inhibitors in the treatment and prevention of disease.
1. A method for inhibiting activity of a type III secretion system of a bacterium, comprising contacting a bacterium having a type III secretion system with an effective amount of at least one compound that inhibits a type III secretion system, wherein the at least one compound is a compound of the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R9 is selected from the group consisting of:
—(C1-C5)alkyl,
—(C1-C5)alkyl-CO 2 H, and
wherein R12 is -halogen,
R10 is selected from the group consisting of:
-hydrogen,
—(C1-C6)alkyl, and
—O—(C1-C6)alkyl;
R11 is selected from the group consisting of:
wherein R13 is -hydrogen or —(C1-C6)alkyl.
2. The method of claim 1 , wherein the at least one compound has a structure selected from the group consisting of:
3. The method of claim 1 , wherein the bacterium is a Yersinia species.
4. The method of claim 3 , wherein the Yersinia species is Yersinia pestis, Yersinia pseudotuberculosis , or Yersinia enterocolitica.
5. The method of claim 1 , wherein the bacterium is selected from the group consisting of: Yersinia pestis, Yersinia enterocolitica, Yersinia pseudotuberculosis, Salmonella enterica, Escherichia coli, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Pseudomonas aeruginosa, Burkholderia pseudomallei, Vibrio parahaemolyticus, Vibrio cholerae, Chlamydia trachomatis, Chlamydia pneumoniae , and Chlamydia psittaci.
6. The method of claim 1 , wherein the bacterium is in a subject.
7. The method of claim 6 , wherein the subject has a disease, or is at risk of a disease, caused by the bacterium.
8. The method of claim 7 , wherein the disease is selected from the group consisting of: bubonic plague, pneumonic plague, septicemic plague, enterocolitis, mesenteric lymphadenitis, typhlitis, typhoid-like disease, enteric fever, intestinal inflammation, bacteremia, septicemia, bloody diarrhea, renal failure, septic shock, bacillary dysentery (shigellosis), sporadic dysentery, whooping cough, kennel cough, atrophic rhinitis, respiratory illness, pneumonia, chronic airway infection, urinary tract infection, clinical infections, melioidosis, noninflammatory secretory diarrhea, inflammatory diarrhea, sexually transmitted infection, and psittacosis.
9. The method of claim 6 , wherein the subject is a human.
10. The method of claim 1 , wherein the bacterium is a biowarfare agent.
11. A method for treating a subject that has a disease, or is at risk of having a disease, caused by a bacterium that has a type III secretion system, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R9 is selected from the group consisting of:
—(C1-C5)alkyl,
—(C1-C5)alkyl-CO 2 H, and
wherein R12 is -halogen,
R10 is selected from the group consisting of:
-hydrogen,
—(C1-C6)alkyl, and
—O—(C1-C6)alkyl;
R11 is selected from the group consisting of:
wherein R13 is -hydrogen or —(C1-C6)alkyl
thereby treating a subject that has a disease, or is at risk of having a disease, caused by a bacterium that has a type III secretion system.
12. The method of claim 11 , wherein the at least one compound is selected from the group consisting of:
13. The method of claim 11 , wherein the bacterium is a Yersinia species.
14. The method of claim 13 , wherein the Yersinia species is Yersinia pestis, Yersinia pseudotuberculosis , or Yersinia enterocolitica.
15. The method of claim 11 , wherein the bacterium is selected from the group consisting of: Yersinia pestis, Yersinia enterocolitica, Yersinia pseudotuberculosis, Salmonella enterica, Escherichia coli, Shigella dysenteriae, Shigella flexneri, Shigella boydii, Shigella sonnei, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Pseudomonas aeruginosa, Burkholderia pseudomallei, Vibrio parahaemolyticus, Vibrio cholerae, Chlamydia trachomatis, Chlamydia pneumoniae , and Chlamydia psittaci.
16. The method of claim 11 wherein the disease is selected from the group consisting of: bubonic plague, pneumonic plague, septicemic plague, enterocolitis, mesenteric lymphadenitis, typhlitis, typhoid-like disease, enteric fever, intestinal inflammation, bacteremia, septicemia, bloody diarrhea, renal failure, septic shock, bacillary dysentery (shigellosis), sporadic dysentery, whooping cough, kennel cough, atrophic rhinitis, respiratory illness, pneumonia, chronic airway infection, urinary tract infection, clinical infections, melioidosis, noninflammatory secretory diarrhea, inflammatory diarrhea, sexually transmitted infection, and psittacosis.
17. The method of claim 11 , wherein the bacterium is a biowarfare agent.