Peptide-based quorum sensing inhibitors for the attenuation of virulence in Staphylococcus aureus

Patent metadata

Field	Value
Publication number	US-9227996-B2
Application number	US-201314109193-A
Country	US
Kind code	B2
Filing date	Dec 17, 2013
Priority date	Mar 11, 2013
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

Compounds that affect quorum sensing (QS) in Staphylococcus aureus and related Staphylococcus species (e.g., S. epidermidis ). Compounds which modulate one or more of the four AgrC receptors of Staphylococcus species, particularly of Staphylococcus aureus . Modulation includes inhibition or activation of one or more of these four AgrC receptors. These compounds are useful for bacterial interference and are useful for treating bacterial infections, particularly staphylococcal infection. Treatment can include combination of one or more of the compounds of the invention in combination with one or more antibiotics.

First claim

The invention claimed is:

1. A compound of formula:

or salts thereof where:
R 1 and R 2 are iso-butyl groups;
R 3 is a benzyl group;
R 4 is selected from a C1-C3 alkyl group or a —CH 2 —COOH group, and
R 12 and R′ 12 are independently selected from a C1-C4 alkyl group, a —CH 2 —CO—NH 2 group or a —CH 2 —CH 2 —CO—NH 2 group; and

wherein each amino acid is an L-amino acid.

2. The compound or salt of claim 1 , wherein R 4 is a —CH 2 —COOH group.

3. The compound or salt of claim 1 , wherein R 4 is a methyl group.

4. The compound or salt of claim 1 , wherein R′ 12 is a C1-C4 alkyl group.

5. The compound or salt of claim 1 , wherein R′ 12 is a methyl group.

6. The compound or salt of claim 1 , wherein R 12 is a sec-butyl group.

7. The compound or salt of claim 1 , wherein R′ 12 is a —CH 2 —CH 2 —CO—NH 2 group.

8. The compound or salt of claim 1 , wherein R 12 is a C1-C4 alkyl group.

9. The compound or salt of claim 1 , wherein R 12 is a methyl group.

10. The compound or salt of claim 1 , wherein R 12 is a sec-butyl group.

11. The compound or salt of claim 1 , wherein R 12 is a —CH 2 —CH 2 —CO—NH 2 group.

12. The compound or salt of claim 1 , wherein R′ 12 is sec-butyl, and R 12 is a —CH 2 —CH 2 —CO—NH 2 group.

13. The compound or salt of claim 1 , wherein R′ 12 is methyl, and R 12 is a —CH 2 —CH 2 —CO—NH 2 group.

14. The compound or salt of claim 1 , wherein R′ 12 is sec-butyl group, and R 12 is a methyl group.

15. The compound or salt of claim 1 , wherein R′ 12 and R 12 are both methyl groups.

16. The compound or salt of claim 1 , wherein R′ 12 is sec-butyl, R 12 is a —CH 2 —CH 2 —CO—NH 2 group, and R 4 is a —CH 2 —COOH group.

17. The compound or salt of claim 1 , wherein R′ 12 is a sec-butyl group, R 12 is a —CH 2 —CH 2 —CO—NH 2 group, and R 4 is a methyl group.

18. The compound or salt of claim 1 , wherein R′ 12 is a methyl group, R 12 is a —CH 2 —CH 2 —CO—NH 2 group, and R 4 is a methyl group.

19. The compound or salt of claim 1 , wherein R′ 12 is a sec-butyl group, R 12 is a methyl group, and R 4 is a methyl group.

20. The compound or salt of claim 1 , wherein R′ 12 is a methyl group, R 12 is a methyl group, and R 4 is a methyl group.

21. A pharmaceutical composition which comprises a therapeutically effective amount of one or more compounds or salts of claim 1 and a pharmaceutically acceptable carrier.

22. A method for attenuating virulence in Staphylococcus which comprises the step of contacting the bacterium with one or more compounds or salts selected from the compounds or salts of claim 1 .

23. The method of claim 22 , wherein the production of toxic shock syndrome toxin-1 is attenuated.

24. A method of treating staphylococcal infection which comprises administering to an individual in need of treatment a therapeutically effective amount of one or more compounds or salts of claim 1 .

25. The method of claim 24 , wherein the staphylococcal infection is a Staphylococcus aureus infection.

26. The method of claim 25 , wherein the infection is toxic shock syndrome.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Blackwell Helen
• Tal-Gan Yftah
• Stacy Danielle

Classifications

• C07K5/12 Primary

  Cyclic peptides {with only normal peptide bonds in the ring} · CPC title

• C07K5/0202

  containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids · CPC title

• C07K7/56 Primary

  the cyclisation not occurring through 2,4-diamino-butanoic acid · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title

• C07K5/021

  containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds · CPC title