Modified beta-lactamases and methods and uses related thereto
Inventors
Koski, Pertti • Airaksinen, Ulla • Valimaki, Katja
Assignees
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Publication Number
US-11214787-B2
Publication Date
2022-01-04
Expiration Date
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.
Core Innovation
The invention relates to a modified Bacillus licheniformis P1A-derived class A beta-lactamase (Ipsat P3A) with an Ambler-position 276 substitution in which aspartic acid (D) is replaced by a hydrophilic amino acid residue. The hydrophilic residue is described as asparagine (N) and/or glutamine (Q), and the partial content specifically highlights D276N and D276R as the noted substitutions. The substitution is positioned with structural context at Ambler position 276 and is described as occurring in an alpha helix (α helix 11).
The modified beta-lactamase is directed to gut-targeted beta-lactamase therapy to prevent antibiotic-induced adverse effects. The partial content states that the approach requires stability in the GIT and an extended substrate profile, including activity across a set of beta-lactam antibiotics. Sequence identity relative to SEQ ID NO: 1 and positional information support the selected hydrophilic residue location at Ambler position 276.
The partial content states that D276N shows markedly improved catalytic efficiency for certain cephalosporins, preferably cefoperazone and especially ceftriaxone, compared with wild type, with kinetic parameters summarized. D276R similarly supports an extended beta-lactam spectrum with differential activity. In a beagle jejunum model, oral enteric-coated D276N beta-lactamase pellets are described as reducing jejunal ceftriaxone concentrations after parenteral ceftriaxone dosing.
Claims Coverage
The partial content provides two independent claims: one directed to a composition and one directed to an oral pharmaceutical composition. Each independent claim is centered on a beta-lactamase defined by sequence identity to SEQ ID NO: 1 and a hydrophilic, non-aspartic-acid residue at the Ambler position corresponding to 276 selected from asparagine (N) and glutamine (Q).
A beta-lactamase with sequence identity and a hydrophilic residue at Ambler position 276
A composition comprising a beta-lactamase comprising an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and a hydrophilic amino acid residue other than aspartic acid (D) at the position corresponding to position 276 according to Ambler classification, wherein the hydrophilic amino acid residue is selected from asparagine (N) and glutamine (Q).
An oral pharmaceutical composition for preventing exposure of cephalosporins in the gastrointestinal tract
A pharmaceutical composition for oral administration comprising an effective amount of a beta-lactamase comprising an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and a hydrophilic amino acid residue other than aspartic acid (D) at the position corresponding to position 276 according to Ambler classification, wherein the hydrophilic amino acid residue is selected from asparagine (N) and glutamine (Q).
Across the independent claims, the key inventive concept is the use of a SEQ ID NO: 1-referenced beta-lactamase variant containing a hydrophilic residue (asparagine or glutamine) at Ambler position 276 instead of aspartic acid, with the second independent claim specifying an oral pharmaceutical composition comprising an effective amount of the beta-lactamase.
Stated Advantages
Improved catalytic efficiency for certain cephalosporins, particularly ceftriaxone, for the D276N substituted beta-lactamase versus wild type.
Extended beta-lactam spectrum supported by D276R, with differential activity.
Reduced jejunal ceftriaxone concentrations in a beagle jejunum model after parenteral ceftriaxone dosing when using oral enteric-coated D276N beta-lactamase pellets.
Documented Applications
Gut-targeted beta-lactamase therapy to prevent antibiotic-induced adverse effects by acting in the gastrointestinal tract (GIT).
Use in a preclinical beagle jejunum model to reduce jejunal ceftriaxone concentrations after parenteral ceftriaxone dosing using oral enteric-coated D276N beta-lactamase pellets.
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