Modified beta-lactamases and methods and uses related thereto

Patent metadata

Field	Value
Publication number	US-9765320-B2
Application number	US-201615138767-A
Country	US
Kind code	B2
Filing date	Apr 26, 2016
Priority date	May 24, 2010
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention relates to pharmaceuticals and modified beta-lactamases. Specifically, the invention relates to novel recombinant beta-lactamases and pharmaceutical compositions comprising the beta-lactamases.
Also, the present invention relates to methods for modifying a beta-lactamase, producing the beta-lactamase and treating or preventing beta-lactam antibiotic induced adverse effects. Furthermore, the present invention relates to the beta-lactamase for use as a medicament and to the use of the beta-lactamase in the manufacture of a medicament for treating or preventing beta-lactam antibiotics induced adverse effects.
Still further, the invention relates to a polynucleotide and a host cell comprising the polynucleotide.

First claim

The invention claimed is:

1. A method for reducing the likelihood of antibiotic-associated diarrhea in a subject, comprising administering an effective amount of a beta-lactamase to the subject wherein:
the subject is receiving a beta-lactam antibiotic, the beta-lactam antibiotic being a substrate of the beta-lactamase;
the antibiotic-associated diarrhea is caused by unabsorbed beta-lactam antibiotic in the intestinal tract; and
the beta-lactamase comprises an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 1 and an asparagine (N) or arginine (R) residue at a position corresponding to position 276 according to Ambler classification and the beta-lactamase hydrolyzes ceftriaxone substantially more efficiently than a beta-lactamase of SEQ ID NO: 1 that has an aspartic acid (D) at a position corresponding to position 276 according to Ambler classification.

2. The method of claim 1 , wherein the beta-lactamase hydrolyses a penicillin and a cephalosporin.

3. The method of claim 2 , wherein the cephalosporin is selected from cefoperazone and ceftriaxone.

4. The method of claim 1 , wherein the beta-lactamase is administered simultaneously to or sequentially with the beta-lactam antibiotic.

5. The method of claim 4 , wherein the beta-lactamase is administered before the beta-lactam antibiotic.

6. The method of claim 1 , wherein the beta-lactamase is administered orally.

7. The method of claim 1 , wherein the beta-lactam antibiotic is administered by intravenous injection.

8. The method of claim 1 , wherein the beta-lactam antibiotic is selected from penicillin and cephalosporin.

9. The method of claim 8 , wherein the cephalosporin is selected from cefoperazone and ceftriaxone.

10. The method of claim 1 , wherein the amino acid sequence has at least 93% sequence identity with SEQ ID NO: 1.

11. The method of claim 1 , wherein the amino acid sequence has at least 95% sequence identity with SEQ ID NO: 1.

12. The method of claim 1 , wherein the beta-lactamase comprises an amino acid sequence of SEQ ID NO: 1 with an asparagine (N) residue at position 276 according to Ambler classification.

13. The method of claim 1 , wherein the beta-lactamase comprises an amino acid sequence of SEQ ID NO: 1 with an arginine (R) residue at position 276 according to Ambler classification.

14. The method of claim 1 , wherein the method maintains an ecological balance of normal intestinal microbiota.

Assignees

• Synthetic Biologics Inc

Inventors

• Koski Pertti
• Airaksinen Ulla
• Valimaki Katja

Classifications

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C12N9/86 Primary

  acting on amide bonds in cyclic amides, e.g. penicillinase {(3.5.2)} · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61K31/43

  Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems · CPC title