Modified lantibiotics and methods of making and using the modified lantibiotics

Patent metadata

Field	Value
Publication number	US-11225510-B2
Application number	US-202016806641-A
Country	US
Kind code	B2
Filing date	Mar 2, 2020
Priority date	Oct 28, 2016
Publication date	Jan 18, 2022
Grant date	Jan 18, 2022

Abstract

The subject invention pertains to a modified lantibiotic containing an intact cysteine at the C-terminus, particularly, a cysteine that is not decarboxylated and that contains a free carboxyl group. Derivatives of the modified lantibiotic comprising a moiety conjugated to the carboxyl group of the terminal cysteine are also provided. A bacterium that produces a modified lantibiotic having an intact cysteine at the C-terminus are also provided, wherein the bacterium is genetically modified to inactivate a gene that encodes a decarboxylase enzyme that decarboxylates the cysteine at the C-terminus of a precursor lantibiotic. Methods of producing a modified lantibiotic having an intact cysteine at the C-terminus by culturing a bacterium that synthesizes the modified lantibiotic and purifying the lantibiotic are also provided. Mutants of lantibiotics, particularly, mutacin 1140 having higher anti-bacterial activity or higher bacterial expression compared to mutacin 1140 are also provided.

First claim

We claim:

1. A method of treating a Gram-positive bacterial infection in a subject by administering to the subject a mutant mutacin 1140 lantibiotic comprising SEQ ID NO: 24 or a pharmaceutical composition comprising said mutant mutacin 1140 lantibiotic and a pharmaceutically acceptable carrier, said mutant mutacin 1140 lantibiotic having an amino acid mutation at position 2 in which the lysine residue is substituted with an alanine.

2. The method of claim 1 , wherein a pharmaceutical composition comprising said mutant mutacin 1140 lantibiotic is administered.

3. The method of claim 1 , wherein said mutant mutacin 1140 lantibiotic is administered.

4. The method of claim 1 , wherein a mutant mutacin 1140 lantibiotic comprising SEQ ID NO: 24 and having an amino acid mutation at position 2 in which the lysine residue is substituted with an alanine is administered in combination with a mutant mutacin 1140 lantibiotic comprising SEQ ID NO: 24 and having an amino acid substitution at position 13 in which the arginine residue is substituted with an alanine.

5. The method of claim 1 , wherein a pharmaceutical composition comprising a mutant mutacin 1140 lantibiotic comprising SEQ ID NO: 24 and having an amino acid mutation at position 2 in which the lysine residue is substituted with an alanine is administered in combination with a mutant mutacin 1140 lantibiotic comprising SEQ ID NO: 24 and having an amino acid substitution at position 13 in which the arginine residue is substituted with an alanine.

Assignees

• Texas A & M Univ Sys

Inventors

• Smith James L
• Escano Jerome

Classifications

• C07K14/315 Primary

  from Streptococcus (G), e.g. Enterococci · CPC title

• C12Y401/01

  Carboxy-lyases (4.1.1) · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C12N9/88

  Lyases (4.) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title