LANTIBIOTIC VARIANTS AND USES THEREOF

• US 20190315814A1
• Filed: 07/14/2017
• Published: 10/17/2019
• Est. Priority Date: 07/15/2016
• Status: Active Application

• Current Assignee: Eleszto Genetika Inc.
• Original Assignee: Intrexon Corporation
• Inventors: HANDFIELD, Martin, KERS, Johan Anthony, MULEY, Sheela, MAYO, Melissa, COLBECK, Jeffrey, SHARP, Robert Eryl, FOSMOE, II, Albert G., DEFUSCO, Anthony W.
• Application Number:
  US16/316,328
• Publication Number:
  US 20190315814A1
• Time in Patent Office: Days
• CPC Class Codes: A01N 63/50 Isolated enzymes; Isolated proteins peptides A01N37/46
• CPC Class Codes: A61K 38/164 from bacteria
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0058 Chewing gums non-medicinal aspects, preparing chewing gum A23G4/00; chewing gum for care of the teeth or oral cavity, e.g. with breath freshener A61Q11/00
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: C07K 14/315 from Streptococcus (G), e.g. Enterococci
• CPC Class Codes: C07K 5/02 containing at least one abnormal peptide link
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The disclosure relates to lantibiotic structural variants that have improved antimicrobial properties when compared to wild-type lantibiotics, and uses thereof. Embodiments include non-naturally occurring lantibiotics.

Claims

1. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising a mutation including:

a. arginine at position 13 changed to asparagine (R13N);

b. phenylalanine at position 17 changed to leucine (F17L) or tyrosine (F17Y);

c. asparagine at position 18 changed to alanine (N18A);

d. tyrosine at position 20 changed to phenylalanine (Y20F);

or

e. combinations thereof.

47. An antimicrobial composition comprising a non-naturally occurring lantibiotic of any one of claims 1 to 26 or 33 to 46 and a pharmaceutically acceptable carrier, pharmaceutically acceptable diluent, other diluent or excipient.

48. The antimicrobial composition of claim 47, further comprising an antifungal agent, an additional antimicrobial agent, a membrane disrupting agent, or a combination thereof.

49. The antimicrobial composition of claim 48, wherein the additional antimicrobial agent has Gram negative bacteriostatic or bacteriocidal activity and the membrane disrupting agent renders Gram negative bacteria susceptible to the variant lantibiotic.

50. The antimicrobial composition of any one of claims 47 to 49, wherein the non-naturally occurring lantibiotics is 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, or 1,000 mg/kg or mg/L.

51. A method of reducing reproduction of bacteria or reducing numbers of bacteria present in or on a subject, comprising administering to the subject a therapeutically effective amount of the antimicrobial composition of any one of claims 47 to 50.

52. The method of claim 51, wherein the subject is a human.

53. The method of claim 47 or 52, wherein the composition is administered orally, topically, nasally, buccally, sublingually, transmucosally, rectally, transdermally, by inhalation, by injection or intrathecally.

54. The method of claim 53, wherein the injection is intramuscular, intravenous, intrapulmonary, intramuscular, intradermal, intraperitoneal, intrathecal, or subcutaneous injection.

55. A preservative comprising an effective amount of the non-naturally occurring lantibiotic of any one of claims 1 to 26 or 33 to 46 in a physiological solution at a pH of between 3 and 8.

56. A food, beverage, gum, or dentifrice composition comprising an amount of the non-naturally occurring lantibiotic of any one of claims 1 to 26 or 33 to 46 sufficient to reduce the reproduction of bacteria or numbers of bacteria in the composition.

57. 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 any one of claims 1 to 26 or 33 to 46 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.

58. The method of claim 57, wherein the composition is a food, beverage, gum, or dentifrice.

59. A composition comprising a solid surface or a textile with the lantibiotic composition of any one of claims 1 to 26 or 33 to 46 or coated onto, immobilized, linked, or bound to the solid surface or textile.

60. A method of reducing a biofilm or biofouling condition comprising contacting the antimicrobial composition of any one of claims 47 to 50 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.

61. A kit comprising the lantibiotic of any one of claims 1 to 26 or 33 to 46 and one or more applicators.

62. A method of preventing or treating a subject diagnosed with a bacterial infection, comprising administering the non-naturally occurring lantibiotic of any one of claims 1 to 26 or 33 to 46.

63. The method of claim 62, wherein the subject is a human.

64. The method of claim 62 or 63, wherein the subject is infected with a Gram-positive bacteria.

65. The method of claim 64, wherein the Gram-positive bacteria is one or more of Staphylococcus epidermidis, vancomycin resistant Enterococci, vancomycin resistant Enterococcus faecalis, Enterococcus faecalis, Enterococcus faecium, Propionibacterium acnes, Streptococcus salivarius, Streptococcus sanguis, Streptococcus mitis, Streptococcus pyogenes, Lactobacillus salivarius, Listeria monocytogenes, Actinomyces israelii, Actinomyces naeslundii, Actinomyces viscosus, Bacillus anthracis, Streptococcus agalactiae, Streptococcus intermedius, Streptococcus pneumoniae, Corynebacterium diphtheria, Clostridium sporogenes Clostridium botulinum, Clostridium perfringens, Clostridium tetani, or Clostridium difficile.

66. The method of claim 65, wherein the Gram-positive bacteria is Clostridium difficile.

67. The method of claim 62 or 63, wherein the subject is infected with a Gram-negative bacteria.

68. The method of claim 67, wherein the Gram-negative bacteria is one or more of Acinetobacter baumanii, Bordatella pertussis, Borrelia burgdotieri, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Coxiella burnetii, Escherichia coli, Francisella tularensis, Haemophilus influenza, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella enteritidis, Salmonella typhi, Salmonella typhimurium, Serratia marcescens, Shigella sonnei, Treponema pallidum, Vibrio cholera, Yersinia enterocolitica, or Yersinia pestis.

69. The method of any one of claims 62 to 68, wherein the non-naturally occurring lantibiotic further comprises one or more additional antimicrobial agents, membrane disrupting agents, or combinations thereof.

71. The antimicrobial composition of claim 47, further comprising an antifungal agent, an additional antimicrobial agent, a membrane disrupting agent, or a combination thereof.

72. The antimicrobial composition of claim 48, wherein the additional antimicrobial agent has Gram negative bacteriostatic or bacteriocidal activity and the membrane disrupting agent renders Gram negative bacteria susceptible to the variant lantibiotic.

103. An isolated recombinant Streptococcus mutans strain comprising:

(a) a mutation in a polynucleotide involved in lactic acid synthesis such that expression of lactic acid is diminished by about 80% or more as compared to a wildtype S. mutans strain;

(b) a recombinant alcohol dehydrogenase polynucleotide; and

(c) a recombinant polynucleotide encoding the non-naturally occurring lantibiotic of any one of claims 1 to 26 or 33 to 46

2. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising two mutations, wherein one mutation includes:

a. arginine at position 13 changed to asparagine (R13N);

b. phenylalanine at position 17 changed to leucine (F17L) or tyrosine (F17Y);

c. asparagine at position 18 changed to alanine (N18A);

d. tyrosine at position 20 changed to phenylalanine (Y20F);

or

e. combinations thereof.

3. The non-naturally occurring lantibiotic of claim 2, wherein one mutation is arginine at position 13 changed to asparagine (R13N).

4. The non-naturally occurring lantibiotic of claim 2 or 3, wherein one mutation is phenylalanine at position 1 changed to valine (F1V).

5. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising two mutations, wherein one mutation includes:

a. phenylalanine at position 1 changed to valine (F1V);

b. phenylalanine at position 1 changed to alanine (F1A);

c. phenylalanine at position 1 changed to isoleucine (F1I);

d. phenylalanine at position 1 changed to leucine (F1L);

e. phenylalanine at position 1 changed to threonine (F1T);

or

f. phenylalanine at position 1 changed to tyrosine (F1Y).

6. The non-naturally occurring lantibiotic of claim 5, wherein one mutation is phenylalanine at position 1 changed to valine (F1V).

7. The non-naturally occurring lantibiotic of claim 5 or 6, wherein one mutation is arginine at position 13 changed to asparagine (R13N).

8. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising two mutations including:

a. phenylalanine at position 1 changed to alanine in combination with arginine at position 13 changed to;

i. alanine (F1A R13A),

ii. valine (F1A R13V),

iii. asparagine (F1A R13N), or

iv. serine(F1A R13S);

b. phenylalanine at position 1 changed to glycine in combination with arginine at position 13 changed to;

i. glycine (F1G R13G);

c. phenylalanine a position 1 changed to histidine in combination with arginine at position 13 changed to;

i. asparagine (F1H R13N);

d. phenylalanine at position 1 changed to isoleucine in combination with arginine at position 13 changed to;

i. alanine (F1I R13A),

ii. glycine (F1I R13G),

iii. isoleucine (F1I R13I),

iv. asparagine (F1I R13N),

v. proline (F1I R13P),

vi. glutamine (F1I R13Q),

vii. glutamic acid (F1I R13S),

viii. serine (F1R13V), or

ix. valine (F1I R13E);

e. phenylalanine at position 1 changed to leucine in combination with arginine at position 13 changed to;

i. alanine (F1L R13A),

ii. aspartic acid (F1L R13D),

iii. glycine (F1L R13G),

iv. asparagine (F1L R13N),

v. proline (F1L R13P), or

vi. glutamine (F1L R13Q);

f. phenylalanine at position 1 changed to threonine in combination with arginine at position 13 changed to;

i. alanine (F1T R13A),

ii. asparagine (F1T R13N), or

iii. valine (F1T R13V);

g. phenylalanine at position 1 changed to valine in combination with arginine at position 13 changed to;

i. alanine (F1V R13A),

ii. asparagine (F1V R13N),

iii. glutamine (F1V R13Q),

iv. aspartic acid (F1V R13D),

v. valine (F1V R13V), or

vi. proline (F1V R13P);

or

h. phenylalanine at position 1 changed to tyrosine in combination with arginine at position 13 changed to;

i. aspartic acid (F1Y R13D), or

ii. glycine (F1Y R13G).

9. The non-naturally occurring lantibiotic of claim 8, comprising two mutations including phenylalanine at position 1 changed to valine in combination with arginine at position 13 changed to:

i. alanine (F1V R13A),

ii. asparagine (F1V R13N),

iii. glutamine (F1V R13Q),

iv. aspartic acid (F1V R13D),

v. valine (F1V R13V), or

vi. proline (F1V R13P).

10. The non-naturally occurring lantibiotic of claim 9, wherein the two mutations consist of phenylalanine at position 1 changed to valine in combination with arginine at position 13 changed to asparagine (F1V R13N).

11. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising three mutations including:

a. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to alanine, in combination with glycine at position 15 changed to alanine (F1I R13A G15A);

b. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to aspartic acid, in combination with glycine at position 15 changed to alanine (F1I R13D G15A);

c. phenylalanine at position 1 changed to isoleucine, in combination with tryptophan at position 4 changed to isoleucine, in combination with arginine at position 13 changed to alanine (F1I W4I R13A);

d. phenylalanine at position 1 changed to isoleucine, in combination with tryptophan at position 4 changed to methionine, in combination with arginine at position 13 changed to aspartic acid (F1I W4M R13D);

e. phenylalanine at position 1 changed to isoleucine, in combination with tryptophan at position 4 changed to methionine, in combination with arginine at position 13 changed to asparagine (F1I W4M R13N);

f. phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with arginine at position 13 changed to alanine (F1I K2A R13A);

g. phenylalanine at position 1 changed to isoleucine, in combination with leucine at position 6 changed to valine, in combination with arginine at position 13 changed to alanine (F1I L6V R13A);

h. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to alanine, in combination with tyrosine at position 20 changed to phenylalanine (F1I R13A Y20F);

i. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to aspartic acid, in combination with tyrosine at position 20 changed to phenylalanine (F1I R13D Y20F);

j. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to asparagine, in combination with tyrosine at position 20 changed to phenylalanine (F1I R13N Y20F);

k. phenylalanine at position 1 changed to leucine, in combination with arginine at position 13 changed to asparagine, in combination with tyrosine at position 20 changed to phenylalanine (F1L R13N Y20F);

l. phenylalanine at position 1 changed to leucine, in combination with arginine at position 13 changed to alanine, in combination with tyrosine at position 20 changed to phenylalanine (F1L R13A Y20F);

or

m. phenylalanine at position 1 changed to leucine, in combination with arginine at position 13 changed to aspartic acid, in combination with tyrosine at position 20 changed to phenylalanine (F1L R13D Y20F).

12. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising mutations wherein:

a. phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with tryptophan at position 4 changed to lysine, in combination with arginine at position 13 changed to alanine (F1I K2A W4K R13A);

or

b. phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with tryptophan at position 4 changed to lysine, in combination with arginine at position 13 changed to aspartic acid (F1I K2A W4K R13D).

13. A non-naturally occurring lantibiotic comprising an amino acid sequence of MU1140 and further comprising mutations wherein phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with tryptophan at position 4 changed to methionine, in combination with arginine at position 13 changed to alanine, in combination with tyrosine at position 20 changed to phenylalanine (F1I K2A W4K R13A Y20F).

14. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising a mutation including;

a. arginine at position 13 changed to asparagine (R13N);

b. phenylalanine at position 17 changed to leucine (F17L) or tyrosine (F17Y);

c. asparagine at position 18 changed to alanine (N18A);

d. tyrosine at position 20 changed to phenylalanine (Y20F);

or

e. combinations thereof.

15. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising two mutations, wherein one mutation includes;

a. arginine at position 13 changed to asparagine (R13N);

b. phenylalanine at position 17 changed to leucine (F17L) or tyrosine (F17Y);

c. asparagine at position 18 changed to alanine (N18A);

d. tyrosine at position 20 changed to phenylalanine (Y20F);

or

e. combinations thereof.

16. The non-naturally occurring, post-translationally modified lantibiotic of claim 15, wherein one mutation is arginine at position 13 changed to asparagine (R13N).

17. The non-naturally occurring, post-translationally modified lantibiotic of claim 15 or 16, wherein one mutation is phenylalanine at position 1 changed to valine (F1V).

18. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising two mutations, wherein one mutation includes;

a. phenylalanine at position 1 changed to valine (F V);

b. phenylalanine at position 1 changed to alanine (F1A);

c. phenylalanine at position 1 changed to isoleucine (F1I);

d. phenylalanine at position 1 changed to leucine (F1L);

e. phenylalanine at position 1 changed to threonine (F1T);

or

f. phenylalanine at position 1 changed to tyrosine (F1Y).

19. The non-naturally occurring, post-translationally modified lantibiotic of claim 18, wherein one mutation is phenylalanine at position 1 changed to valine (F1V).

20. The non-naturally occurring, post-translationally modified lantibiotic of claim 18 or 19, wherein one mutation is arginine at position 13 changed to asparagine (R13N).

21. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising two mutations including;

a. phenylalanine at position 1 changed to alanine in combination with arginine at position 13 changed to;

i. alanine (F1A R13A),

ii. valine (F1A R13V),

iii. asparagine (F1A R13N), or

iv. serine(F1A R13S);

b. phenylalanine at position 1 changed to glycine in combination with arginine at position 13 changed to;

i. glycine (F1G R13G);

c. phenylalanine a position 1 changed to histidine in combination with arginine at position 13 changed to;

i. asparagine (F1H R13N);

d. phenylalanine at position 1 changed to isoleucine in combination with arginine at position 13 changed to;

i. alanine (F1I R13A),

ii. glycine (F1I R13G),

iii. isoleucine (F1I R13I),

iv. asparagine (F1I R13N),

v. proline (F1I R13P),

vi. glutamine (F1I R13Q),

vii. glutamic acid (F1I R13S),

viii. serine (F1I R13V), or

ix. valine (F1I R13E);

e. phenylalanine at position 1 changed to leucine in combination with arginine at position 13 changed to;

i. alanine (F1L R13A),

ii. aspartic acid (F1L R13D),

iii. glycine (F1L R13G),

iv. asparagine (F1L R13N),

v. proline (F1L R13P), or

vi. glutamine (F1L R13Q);

f. phenylalanine at position 1 changed to threonine in combination with arginine at position 13 changed to;

i. alanine (F1T R13A),

ii. asparagine (F1T R13N), or

iii. valine (F1T R13V);

g. phenylalanine at position 1 changed to valine in combination with arginine at position 13 changed to;

i. alanine (F1V R13A),

ii. asparagine (F1V R13N),

iii. glutamine (F1V R13Q),

iv. aspartic acid (F1V R13D),

v. valine (F1V R13V), or

vi. proline (F1V R13P);

or

h. phenylalanine at position 1 changed to tyrosine in combination with arginine at position 13 changed to;

i. aspartic acid (F1Y R13D), or

ii. glycine (F1Y R13G).

22. The non-naturally occurring, post-translationally modified lantibiotic of claim 21, comprising two mutations including phenylalanine at position 1 changed to valine in combination with arginine at position 13 changed to:

i. alanine (F1V R13A),

ii. asparagine (F1V R13N),

iii. glutamine (F1V R13Q),

iv. aspartic acid (F1V R13D),

v. valine (F1V R13V), or

vi. proline (F1V R13P).

23. The non-naturally occurring, post-translationally modified lantibiotic of claim 22, wherein the two mutations consist of phenylalanine at position 1 changed to valine in combination with arginine at position 13 changed to asparagine (F1V R13N) (SEQ ID NO:

550).

24. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising three mutations including;

a. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to alanine, in combination with glycine at position 15 changed to alanine (F1I R13A G15A);

b. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to aspartic acid, in combination with glycine at position 15 changed to alanine (F1I R13D G15A);

c. phenylalanine at position 1 changed to isoleucine, in combination with tryptophan at position 4 changed to isoleucine, in combination with arginine at position 13 changed to alanine (F1I W4I R13A);

d. phenylalanine at position 1 changed to isoleucine, in combination with tryptophan at position 4 changed to methionine, in combination with arginine at position 13 changed to aspartic acid (F1I W4M R13D);

e. phenylalanine at position 1 changed to isoleucine, in combination with tryptophan at position 4 changed to methionine, in combination with arginine at position 13 changed to asparagine (F1I W4M R13N);

f. phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with arginine at position 13 changed to alanine (F1I K2A R13A);

g. phenylalanine at position 1 changed to isoleucine, in combination with leucine at position 6 changed to valine, in combination with arginine at position 13 changed to alanine (F1I L6V R13A);

h. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to alanine, in combination with tyrosine at position 20 changed to phenylalanine (F1I R13A Y20F);

i. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to aspartic acid, in combination with tyrosine at position 20 changed to phenylalanine (F1I R13D Y20F);

j. phenylalanine at position 1 changed to isoleucine, in combination with arginine at position 13 changed to asparagine, in combination with tyrosine at position 20 changed to phenylalanine (F1I R13N Y20F);

k. phenylalanine at position 1 changed to leucine, in combination with arginine at position 13 changed to asparagine, in combination with tyrosine at position 20 changed to phenylalanine (F1L R13N Y20F);

l. phenylalanine at position 1 changed to leucine, in combination with arginine at position 13 changed to alanine, in combination with tyrosine at position 20 changed to phenylalanine (F1L R13A Y20F);

or

m. phenylalanine at position 1 changed to leucine, in combination with arginine at position 13 changed to aspartic acid, in combination with tyrosine at position 20 changed to phenylalanine (F1L R13D Y20F).

25. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising mutations wherein;

a. phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with tryptophan at position 4 changed to lysine, in combination with arginine at position 13 changed to alanine (F1I K2A W4K R13A);

or

b. phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with tryptophan at position 4 changed to lysine, in combination with arginine at position 13 changed to aspartic acid (F1I K2A W4K R13D).

26. A non-naturally occurring, post-translationally modified lantibiotic comprising an amino acid sequence of MU1140 (SEQ ID NO:

1156) and further comprising mutations wherein phenylalanine at position 1 changed to isoleucine, in combination with lysine at position 2 changed to alanine, in combination with tryptophan at position 4 changed to methionine, in combination with arginine at position 13 changed to alanine, in combination with tyrosine at position 20 changed to phenylalanine (F1I K2A W4K R13A Y20F).

27. A non-naturally occurring lantibiotic comprising a single amino acid mutation of MU1140, the lantibiotic having an amino acid sequence encoded by of any one of SEQ ID NOS:

2 to 431.

33. The non-naturally occurring lantibiotic of any one of claim 27 to 32, wherein the lantibiotic is post-translationally modified.

34. The non-naturally occurring lantibiotic of claim 33, wherein the post-translation modification comprises Dha at position 5.

35. The non-naturally occurring lantibiotic of claim 33 or claim 34, wherein the post-translation modification comprises Abu at position 8.

36. The non-naturally occurring lantibiotic of any one of claim 33 to claim 35, wherein the post-translation modification comprises Dhb at position 14.

37. The non-naturally occurring lantibiotic of any one of claim 33 to claim 36, wherein the post-translation modification comprises Dha at position 5, Abu at position 8, and Dhb at position 14.

38. The non-naturally occurring lantibiotic of any one of claim 33 to claim 37, wherein the post-translation modification comprises a ring formed by lanthionine (Ala-S-Ala) residues between (Ala₃-S-Ala₇) as described in FIG. 1 (Ring A).

39. The non-naturally occurring lantibiotic of any one of claim 33 to claim 38, wherein the post-translation modification comprises a methyl-lanthionine residue (Abu-S-Ala) forming a ring, Ring B, comprising the alpha-aminobutyrate residue in position 8 and the Ala in position 11 (Abu₈-S-Ala₁₁) as described in FIG. 1.

40. The non-naturally occurring lantibiotic of any one of claim 33 to claim 39, wherein the post-translation modification comprises a ring formed by lanthionine (Ala-S-Ala) residues between (Ala₁₆-S-Ala₂₁) as described in FIG. 1 (Ring C).

41. The non-naturally occurring lantibiotic of any one of claim 33 to claim 40, wherein the post-translation modification comprises Ala in position 19 linked to an aminovinyl group by a thioether linkage (Ala₁₉-S—

CH═

CH—

NH—

), Ring D, as described in FIG. 1.

42. The non-naturally occurring lantibiotic of any one of claim 33 to claim 41, wherein the post-translation modification comprises Ring A, B, C and D.

43. The non-naturally occurring lantiobiotic of any one of claims 33 to 42, wherein the post-translationally modified MU1140 variant comprises Ring A, Ring B, Ring C and Ring D, wherein:

a. two of these rings are formed by lanthionine (Ala-S-Ala) residues, including one in Ring A (Ala₃-S-Ala₇) and one in Ring C (Ala₁₆-S-Ala₂₁);

b. a methyl-lanthionine residue (Abu-S-Ala) forms Ring B comprising the alpha-aminobutyrate residue in position 8 and the Ala in position 11 (Abu₈-S-Ala₁₁); and

c. the fourth ring, D, is comprised of the Ala in position 19 linked to an aminovinyl group by a thioether linkage (Ala₁₉-S—

CH═

CH—

NH—

).

and wherein amino acid at position 5 is modified to Dha, the amino acid at position 8 is modified to Abu, and the amino acid at position 14 is modified to Dhb.

28. A non-naturally occurring lantibiotic comprising multisite amino acid mutations of MU1140, the lantibiotic being a variant as described in FIG. 7.

29. A non-naturally occurring lantibiotic comprising any variant as described in FIG. 8:

Group 1, Group 2 or Group 3.

30. A non-naturally occurring lantibiotic comprising any variant as described in FIG. 8:

Group 1.

31. A non-naturally occurring lantibiotic comprising a single amino acid mutation of MU1140 as described in FIG. 6.

32. A non-naturally occurring lantibiotic comprising an amino acid sequence of SEQ ID NO. 550.

44. An isolated lantibiotic variant, wherein the isolated lantibiotic variant is produced in a host cell by expressing a polypeptide from a polynucleotide encoding a lantibiotic variant of FIG. 5 or FIG. 7, and wherein the expressed polypeptide is post-translationally modified in the host cell.

45. The isolated lantibiotic variant of claim 44, wherein the host cell is S. mutans.

46. A post-translationally modified, non-naturally occurring lantibiotic comprising an amino acid sequence of SEQ ID NO. 1157.

70. An antimicrobial composition, comprising the non-naturally occurring lantibiotic of claim 46, and a pharmaceutically acceptable carrier, pharmaceutically acceptable diluent, other diluent, excipient, or combinations thereof.

73. The antimicrobial composition of any one of claims 70 to 72, wherein the non-naturally occurring lantibiotic is 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, or 1,000 mg/kg or mg/L.

74. A method of reducing reproduction of bacteria or reducing numbers of bacteria present in or on a subject, comprising administering to the subject a therapeutically effective amount of the antimicrobial composition of any one of claims 70 to 73.

75. The method of claim 74, wherein the subject is a human.

76. The method of claim 73 or 74, wherein the composition is administered orally, topically, nasally, buccally, sublingually, transmucosally, rectally, transdermally, by inhalation, by injection, or intrathecally.

77. The method of claim 75, wherein the injection is intramuscular, intravenous, intrapulmonary, intramuscular, intradermal, intraperitoneal, intrathecal, or subcutaneous injection.

78. A preservative comprising an effective amount of the non-naturally occurring lantibiotic of claim 46 in a physiological solution at a pH of between 3 and 8.

79. A food, beverage, gum, or dentifrice composition comprising an amount of the non-naturally occurring lantibiotic of claim 46 sufficient to reduce the reproduction of bacteria or numbers of bacteria in the composition.

80. A method of reducing reproduction of bacteria or reducing numbers of bacteria present in or on a composition or object, comprising contacting the non-naturally occurring lantibiotic of claim 46 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.

81. The method of claim 80, wherein the composition is a food, beverage, gum, or dentifrice.

82. A composition comprising a solid surface or a textile with the non-natrually occurring lantibiotic of claim 46 or coated onto, immobilized, linked, or bound to the solid surface or textile.

83. A method of reducing a biofilm or biofouling condition comprising contacting the non-naturally occurring lantibiotic of claim 46 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.

84. A kit comprising the lantibiotic of claim 46 and one or more applicators.

85. A method of preventing or treating a subject diagnosed with a bacterial infection, comprising administering the non-naturally occurring lantibiotic of claim 46.

86. The method of claim 85, wherein the subject is a human.

87. The method of claim 85 or 86, wherein the subject is infected with a Gram-positive bacteria.

88. The method of claim 87, wherein the Gram-positive bacteria is one or more of Staphylococcus epidermidis, vancomycin resistant Enterococci, vancomycin resistant Enterococcus faecalis, Enterococcus faecalis, Enterococcus faecium, Propionibacterium acnes, Streptococcus salivarius, Streptococcus sanguis, Streptococcus mitis, Streptococcus pyogenes, Lactobacillus salivarius, Listeria monocytogenes, Actinomyces israelii, Actinomyces naeslundii, Actinomyces viscosus, Bacillus anthracis, Streptococcus agalactiae, Streptococcus intermedius, Streptococcus pneumoniae, Corynebacterium diphtheria, Clostridium sporogenes Clostridium botulinum, Clostridium perfringens, Clostridium tetani, or Clostridium difficile.

89. The method of claim 88, wherein the Gram-positive bacteria is Clostridium difficile.

90. The method of claim 85 or 86, wherein the subject is infected with a Gram-negative bacteria.

91. The method of claim 90, wherein the Gram-negative bacteria is one or more of Acinetobacter baumanii, Bordatella pertussis, Borrelia burgdotieri, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Coxiella burnetii, Escherichia coli, Francisella tularensis, Haemophilus influenza, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Neisseria gonorrhoeae, Neisseria meningitides, Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella enteritidis, Salmonella typhi, Salmonella typhimurium, Serratia marcescens, Shigella sonnei, Treponema pallidum, Vibrio cholera, Yersinia enterocolitica, or Yersinia pestis.

92. The method of any one of claims 85 to 91, wherein the non-naturally occurring lantibiotic further comprises one or more additional antimicrobial agents, membrane disrupting agents, or combinations thereof.

93. A purified polynucleotide comprising any one of SEQ ID NOs:

2-431 or encoding a variant as described in FIG. 7 or combinations thereof.

94. A purified polynucleotide comprising any one of SEQ ID NOs:

756, 757, 758, 759, or 760.

95. A purified polynucleotide comprising any one of SEQ ID NOs:

709, 714, 716, 735, 747, 751, 754, or 758.

96. A purified polynucleotide comprising SEQ ID NO:

758.

97. A purified polynucleotide comprising SEQ ID NO:

1163.

98. A host cell comprising a polynucleotide of SEQ ID NO:

758.

99. A host cell comprising a polynucleotide of SEQ ID NO:

1163.

100. An isolated recombinant Streptococcus mutans strain comprising a polynucleotide of SEQ ID NO:

758.

101. An isolated recombinant Streptococcus mutans strain comprising a polynucleotide of SEQ ID NO:

1163.

102. A non-naturally occurring polypeptide comprising an amino acid sequence of SEQ ID NO. 1161.