Synthetic ligands that modulate the activity of the RhlR quorum sensing receptor
RhlR modulators including agonist and antagonists which are useful for modulating QS phenotypes in Gram-negative bacteria. Certain compounds of general formula A-W-HG having various carbocyclic ad heterocyclic head groups (HG) and various tail groups (A), where —W— is —CO—NH—, —SO 2 —NH—, —CO—NH—CH 2 —, or —SO 2 —NH—CH 2 — are RhlR agonists or antagonists. The compounds are useful in methods of modulating quorum sensing in Gram-negative bacteria, particularly in Pseudomonas . Compositions including certain RhlR modulators are useful for decreasing the virulence of Gram-negative bacteria. Pharmaceutical compositions comprising certain RhlR modulators are useful for treatment of infections of Gram-negative bacteria.
1. A compound of formula:
A-W-HG
where:
—W— is —CO—NH—, —SO 2 —NH—, —CO—NH—CH 2 —, or —SO 2 —NH—CH 2 —;
A is selected from cyclobutyl, and —CH 2 —cyclopropyll and
HG is selected from the group of moieties of formula:
where:
X is CH 2
Y is O or S and
Z is C=O or CH(OH).
2. The compound of claim 1 , wherein X=CH 2 , Y=O and Z=CO or CH(OH).
3. The compound of claim 1 which is:
4. The compound of claim 1 which is:
5. The compound of claim 2 , wherein W is —CO—NH—.
6. The compound of claim 1 , wherein W is —CO—NH—.
7. The compound of claim 1 , wherein HG is:
8. The compound of claim 7 , wherein A is cyclopropyl, cyclobutyl, or CH 2 cyclopropy.
9. The compound of claim 8 , wherein W is —CO—NH—.
10. A compound of formula:
A-W-HG
where:
—W— is —CO—NH—, —SO 2 —NH—, —CO—NH—CH 2 —, or —SO 2 —NH—CH 2 —;
A is selected from cyclopropyl, cyclobutyl, and —CH 2 —cyclopropyl; and
HG is selected from the group of moieties of formula:
where:
X is CH 2
Y is S; and
Z is C=O or CH(OH).
11. The compound of claim 10 , wherein X=CH 2 ; Y=S;
and Z=CO.
12. The compound of claim 10 , wherein A is cyclobutyl or —CH 2 —cyclopropyl.
13. The compound of claim 11 , wherein W is —CO—NH—.
14. The compound of claim 10 , wherein W is —CO—NH—.
15. A method for modulating RhIR of a Gram-negative bacterium which comprises contacting the bacterium with one or more compounds of claim 1 .
16. A method of treating an infection of a Gram-negative bacterium by administering to an individual in need of treatment a therapeutically effective amount of a compound of claim 1 .
17. A method of treating an infection of a Gram-negative bacterium by administering to an individual in need of treatment a therapeutically effective amount of a compound of claim 10 .
18. A method for modulating RhIR of a Gram-negative bacterium which comprises contacting the bacterium with one or more compounds of claim 10 .