Tunicamycin related compounds with anti-bacterial activity

Patent metadata

Field	Value
Publication number	US-10513533-B2
Application number	US-201815872270-A
Country	US
Kind code	B2
Filing date	Jan 16, 2018
Priority date	Jan 26, 2017
Publication date	Dec 24, 2019
Grant date	Dec 24, 2019

Abstract

Tunicamycin related compounds having an acyl chain double bond reduced and/or having an acyl chain double bond and an uracil ring double bond reduced are described as well as methods of making these tunicamycin related compounds. These tunicamycin related compounds are not toxic to eukaryotic cells and can be used to kill Gram-positive bacteria, alone or in combination with other antibiotics. Use of these tunicamycin related compounds to kill Gram-positive bacteria, treat Gram-positive bacterial diseases, and disinfect objects or surfaces are described. In addition, naturally-occurring streptovirudin compounds are not toxic to eukaryotic cells and can be used to kill Gram-positive bacteria, alone or in combination with other antibiotics.

First claim

I, the inventor, claim as follows:

1. A tunicamycin related compound comprising Formula 2

wherein R 2 is Y

wherein R 1 is independently
(i) CH 3 —(CH 2 ) n —CH 2 —CH 2 — and n is independently any integer from 9 to 15, or
(ii) CH 3 —CH 2 —CH(CH 3 )(CH 2 ) n —CH 2 —CH 2 — and n is independently any integer from 6 to 12;

wherein R 2 is Y;
wherein R 3 is independently HOCH 2 —, an alkyl hydrocarbon, or a non-alkyl C 1-10 hydrocarbon;
wherein R 4 is independently H or P—(O)(OH) 2 ; and
wherein R 5 is independently H, F, Cl, Br, I, an alkyl hydrocarbon, or a non-alkyl C 1-10 hydrocarbon.

2. An antibacterial composition comprising at least one of said tunicamycin related compounds of claim 1 .

3. The antibacterial composition of claim 2 , further comprising an antibiotic, wherein said antibiotic is a β-lactam antibiotic, a non-β-lactam antibiotic, or combination thereof.

4. The antibacterial composition of claim 3 , wherein the antibiotic is a β-lactam antibiotic and said β-lactam antibiotic is selected from the group consisting of a penicillin, a cephalosporin, a monobactam, a carbapenem, and a combination thereof.

5. A method of killing Gram-positive bacteria in or on an animal comprising administering to said animal an effective amount of said antibacterial composition of claim 2 .

6. The method of claim 5 , wherein said antibacterial composition of claim 2 further comprises an antibiotic, wherein said antibiotic is a β-lactam antibiotic, a non-β-lactam antibiotic, or combination thereof.

7. The method of claim 6 , wherein said β-lactam antibiotic is selected from the group consisting of a penicillin, a cephalosporin, a monobactam, a carbapenem, and a combination thereof.

8. A method of inhibiting or treating a bacterial infection caused by Gram-positive bacteria in an animal in need to treatment, said method comprising administering to said animal in need of treatment an effective amount of said antibacterial composition of claim 2 .

9. The method of claim 8 , wherein said antibacterial composition of claim 2 further comprises an antibiotic, wherein said antibiotic is a β-lactam antibiotic, a non-β-lactam antibiotic, or combination thereof.

10. The method of claim 9 , wherein said β-lactam antibiotic is selected from the group consisting of a penicillin, a cephalosporin, a monobactam, a carbapenem, and a combination thereof.

11. A method of disinfecting an object or a surface that has Gram-positive bacteria on said object or said surface comprising applying an effective amount of said tunicamycin related compound of claim 1 to said object or said surface in order to kill said Gram-positive bacteria present on said object or said surface.

12. A method of making a tunicamycin related compound of claim 1 comprising
(a) exposing an unmodified tunicamycin to a sufficient amount of a catalyst and a sufficient amount of an agent that hydrogenates double-bonds to single bonds in acidic organic liquid to create a mixture, and
(b) stirring said mixture for approximately 20 hours to approximately 80 hours at a temperature between approximately 50° C. to approximately 95° C. to reduce double bonds in said unmodified tunicamycin's fatty acid acyl chain and uracil ring, thereby generating unpurified tunicamycin related compound of claim 1 .

13. The method of claim 12 , further comprising
(c) allowing said unpurified tunicamycin related compound of claim 1 to cool to approximately room temperature, and
(d) separating said catalyst from said unpurified tunicamycin related compound of claim 1 at approximately room temperature to generate a composition of unpurified tunicamycin related compound of claim 1 without said catalyst.

14. The method of claim 13 , further comprising
(e) suspending said composition of unpurified tunicamycin related compound of claim 1 without said catalyst in an alcohol, and
(f) heating said alcohol suspended unpurified tunicamycin related compound of claim 1 to a sufficient temperature and for a sufficient time to convert any of said agent that hydrogenates double-bonds to single bonds and any of said acid that are present in said alcohol suspended unpurified tunicamycin related compound of claim 1 into volatile organics which are allowed to evaporate, thereby generating said tunicamycin related compound of claim 1 that is purified.

15. An antibacterial composition comprising:
a tunicamycin related compound; and
an antibiotic, wherein said antibiotic is a β-lactam antibiotic, or a combination of a β-lactam antibiotic and a non-β-lactam antibiotic,
wherein the tunicamycin related compound comprises Formula 2

wherein R 2 is Y

wherein R 1 is (CH 3 ) 2 —CH—(CH 2 ) n —CH 2 —CH 2 — and n is independently any integer from 7 to 13;
wherein R 2 is Y;
wherein R 3 is independently HOCH 2 —, an alkyl hydrocarbon, or a non-alkyl C 1-10 hydrocarbon;
wherein R 4 is independently H or P—(O)(OH) 2 ; and
wherein R 5 is independently H, F, Cl, Br, I, an alkyl hydrocarbon, or a non-alkyl C 1-10 hydrocarbon.

16. The antibacterial composition of claim 15 , wherein the antibiotic is a β-lactam antibiotic and said β-lactam antibiotic is selected from the group consisting of a penicillin, a cephalosporin, a monobactam, a carbapenem, and a combination thereof.

17. A method of killing Gram-positive bacteria in or on an animal comprising administering to said animal an effective amount of said antibacterial composition of claim 15 .

18. A method of inhibiting or treating a bacterial infection caused by Gram-positive bacteria in an animal in need to treatment, said method comprising administering to said animal in need of treatment an effective amount of said antibacterial composition of claim 15 .

19. A method of disinfecting an object or a surface that has Gram-positive bacteria on said object or said surface comprising applying an effective amount of a tunicamycin related compound to said object or said surface in order to kill said Gram-positive bacteria present on said object or said surface,
wherein the tunicamycin related compound comprises Formula 2

wherein R 2 is Y

wherein R 1 is (CH 3 ) 2 —CH—(CH 2 ) n —CH 2 —CH 2 — and n is independently any integer from 7 to 13;
wherein R 2 is Y;
wherein R 3 is independently HOCH 2 —, an alkyl hydrocarbon, or a non-alkyl C 1-10 hydrocarbon;
wherein R 4 is independently H or P—(O)(OH) 2 ; and
wherein R 5 is independently H, F, Cl, Br, I, an alkyl hydrocarbon, or a non-alkyl C 1-10 hydrocarbon.

20. A method of making a tunicamycin related compound comprising Formula 2

wherein R 2 is Y

Assignees

• Us Agriculture

Inventors

• Price Neil P

Classifications

• A61K31/7076

  containing purines, e.g. adenosine, adenylic acid · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07H15/207

  Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins · CPC title

• A01N43/16

  with oxygen as the ring hetero atom · CPC title

• A61K31/7034

  attached to a carbocyclic compound, e.g. phloridzin · CPC title