Beta-lactamases with improved properties for therapy
Inventors
Kaleko, Michael • Connelly, Sheila
Assignees
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Publication Number
US-11608494-B2
Publication Date
2023-03-21
Expiration Date
Abstract
This invention relates to, in part, compositions of beta-lactamases and methods of using these enzymes in, for example, gastrointestinal tract (GI tract) disorders such as C. difficile infection (CDI).
Core Innovation
The invention provides a beta-lactamase comprising an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and a mutation at positions 33 and 276, according to Ambler classification. The beta-lactamase is described as derived from the P1A (Bacillus licheniformis PenP) scaffold, with additional Ambler-position mutations including positions 135, 156, 232, 237, 238, 240, 243, 244, 266, and 276.
The invention further frames the beta-lactamase as a functional agent for gastrointestinal protection by preventing an antibiotic-induced adverse effect in the GI tract. The method comprises administering an effective amount of the beta-lactamase to a patient in need thereof, with the goal of maintaining microbiome balance without interfering with systemic antibiotic utility.
The disclosed solution includes pharmaceutical composition and delivery context in the GI tract, including oral administration and enteric-delayed release coating and stability/resistance features. The beta-lactamase is described in the context of formulations using pharmaceutically acceptable carriers/excipients.
Claims Coverage
The partial claim set contains two independent claims, one directed to the beta-lactamase itself and one directed to a prevention method. Across these claims, the core inventive features center on a specific beta-lactamase sequence definition and on using that beta-lactamase to prevent GI antibiotic-induced adverse effects; additional refinements include optional additional Ambler mutations and oral pharmaceutical composition forms.
Defined beta-lactamase sequence identity with Ambler-position mutations
A beta-lactamase comprising an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and a mutation at positions 33 and 276, according to Ambler classification.
Preventing antibiotic-induced adverse effects in the GI tract by administering a defined beta-lactamase
A method for preventing an antibiotic-induced adverse effect in the gastrointestinal (GI) tract, comprising administering an effective amount of a beta-lactamase to a patient in need thereof, wherein the beta-lactamase comprises an amino acid sequence having at least 98% sequence identity with SEQ ID NO: 1 and a mutation at positions 33 and 276, according to Ambler classification.
Overall, the claim coverage is anchored in a beta-lactamase defined by at least 98% sequence identity to SEQ ID NO: 1 together with Ambler-defined mutations at positions 33 and 276. The method claim extends this enzyme definition to prevention of GI antibiotic-induced adverse effects in patients, with further claim refinements targeting specific GI adverse-effect categories and optional additional Ambler-position mutations.
Stated Advantages
Prevents an antibiotic-induced adverse effect in the gastrointestinal (GI) tract.
Prevents antibiotic-induced adverse effects including C. difficile infection (CDI), C. difficile-associated disease, and antibiotic-associated diarrhea (AAD).
Maintains microbiome balance without interfering with systemic antibiotic utility.
Broadens antibiotic substrate coverage for penicillins and cephalosporins and improves enzyme kinetics for cephalosporin hydrolysis and penicillin hydrolysis.
Documented Applications
Preventing antibiotic-induced adverse effects in the gastrointestinal (GI) tract, including C. difficile infection (CDI), C. difficile-associated disease, and antibiotic-associated diarrhea (AAD).
Oral administration of a pharmaceutical composition formulated for use in the GI tract, including oral and enteric-delayed release contexts.
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