Variants of the lantibiotic MU1140 and other lantibiotics with improved pharmacological properties and structural features

Patent metadata

Field	Value
Publication number	US-9963488-B2
Application number	US-201314381420-A
Country	US
Kind code	B2
Filing date	Feb 22, 2013
Priority date	Feb 27, 2012
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The invention provides improvements of lantibiotics useful for reducing the numbers of microbes or the reproduction of microbes in or on subjects or objects. One embodiment of the invention provides variants of antibiotics wherein the amino acid at position (1) is changed to Ile or Gly, the amino acid at position (4) is changed to an Ala, the amino acid at position (4) is removed, the amino acid at position (5) is changed to an Ala, or wherein, as in the case of MU1140, the amino acid at position (13) is Arg, the Arg at position (13) is substituted with Asp, or combinations of two or more these changes or a pharmaceutically acceptable salt thereof.

First claim

We claim:

1. A variant MU1140 lantibiotic comprising Formula I:

wherein the X at position 1 is Gly, the X at position 4 is Trp, the X at position 5 is Dha, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —;
(i) wherein the X at position 1 is Phe, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Dha, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (ii) wherein the X at position 1 is Phe, the X at position 4 is Trp, the X at position 5 is Ala, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (iii) wherein the X at position 1 is Phe, the X at position 4 is Trp, the X at position 5 is Dha, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (iv) wherein the X at position 1 is Gly or Ile, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Dha, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (v) wherein the X at position 1 is Gly or Ile, the X at position 4 is Trp, the X at position 5 is Ala, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (vi) wherein the X at position 1 is Gly or Ile, the X at position 4 is Trp, the X at position 5 is Dha, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (vii) wherein the X at position 1 is Phe, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Ala, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (viii) wherein the X at position 1 is Phe, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Dha, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (ix) wherein the X at position 1 is Phe, the X at position 4 is Trp, the X at position 5 is Ala, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (x) wherein the X at position 1 is Gly or Ile, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Ala, the X at position 13 is Arg, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (xi) wherein the X at position 1 is Gly or Ile, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Dha, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (xii) wherein the X at position 1 is Gly or Ile, the X at position 4 is Trp, the X at position 5 is Ala, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (xiii) wherein the X at position 1 is Phe, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Ala, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —; (xiv) wherein the X at position 1 is Gly or Ile, the X at position 4 is Ala, absent, or both Trp and Ala, the X at position 5 is Ala, the X at position 13 is Asp, the X at position 8 is Abu or Ala, the X at position 14 is Dhb or Ala, and the X at position 22 is —CH═CH— or —CH 2 —CH 2 —;
or a pharmaceutically acceptable salt thereof.

2. An antimicrobial composition comprising one or more isolated variant MU1140 lantibiotics of claim 1 and a pharmaceutically acceptable carrier, pharmaceutically acceptable diluent, other diluent or excipient.

3. The antimicrobial composition of claim 2 , wherein the composition further comprises at least one antifungal agent, one additional antimicrobial agent, a membrane disrupting agent, or combinations thereof.

4. The antimicrobial composition of claim 3 , wherein the one additional antimicrobial agent has Gram negative bacteriostatic or bacteriocidal activity and the membrane disrupting agent renders Gram negative bacteria susceptible to the variant MU1140 lantibiotic.

5. The antimicrobial composition of claim 2 , wherein the one or more isolated MU1140 lantibiotics are present in the composition at about 0.001, 0.01, 0.1, 1, 5, 10, 20, 30, 40, 50, 75, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1,000 or more mg/kg or mg/L.

6. A method of reducing reproduction of bacteria or reducing numbers of bacteria present in or on in a subject, comprising administering to the subject a therapeutically effective amount of the antimicrobial composition of claim 2 .

7. The method of claim 6 , wherein the subject is a human.

8. The method of claim 6 , wherein the composition is administered orally or topically, nasally, buccally, sublingually, transmucosally, rectally, transdermally, by inhalation, by injection or intrathecally.

9. The method of claim 8 , wherein the injection is intramuscular, intravenous, intrapulmonary, intramuscular, intradermal, intraperitoneal, intrathecal, or subcutaneous injection.

10. A preservative comprising an effective amount of one or more variant MU1140 lantibiotics of claim 1 in a physiological solution at a pH of between 3 and 8.

11. A food, beverage, gum, or dentifrice composition comprising an amount of one or more variant MU1140 lantibiotics of claim 1 sufficient to reduce the reproduction of bacteria or numbers of bacteria in the composition.

12. A method of reducing reproduction of bacteria or reducing numbers of bacteria present in or on a composition or object, comprising contacting the antimicrobial composition of claim 10 with the composition or object for a period effective to reduce reproduction of bacteria or reduce numbers of bacteria in or on the composition or object.

13. The method of claim 12 , wherein the composition is a food, beverage, gum, or dentifrice.

14. A purified polynucleotide comprising SEQ ID NOs: 19-26 or combinations thereof.

15. A composition comprising a solid surface or a woven or non-woven textile with the variant MU1140 lantibiotic of claim 1 or coated onto, immobilized, linked, or bound to the solid surface or textile.

16. A method of reducing a biofilm or biofouling condition comprising contacting the variant MU1140 lantibiotic of claim 1 with the biofilm or biofouling condition for a period effective to reduce reproduction of bacteria or reduce numbers of bacteria in or on the biofilm or biofouling condition.

17. A kit comprising one or more variant MU1140 lantibiotics of claim 1 and one or more applicators.

18. A variant MU1140 lantibiotic comprising Formula I:

wherein the X at positio

Assignees

• Oragenics Inc
• Texas A & M Univ Sys

Inventors

• Hillman Jeffrey D
• Smith James Leif
• Wilson-Stanford Shawanda R

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61P1/02

  Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis · CPC title

• A61Q11/00

  Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses · CPC title

• A23L2/52

  Adding ingredients (adding preservatives A23B70/10) · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title