Carbapenemases for use with antibiotics for the protection of the intestinal microbiome

Abstract

This invention relates, in part, to various compositions and methods for protecting the gastrointestinal microbiome from antibiotic disruption.

Description

PRIORITY[0001]This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 62 / 119,602, filed Feb. 23, 2015, 62 / 155,621, filed May 1, 2015, and 62 / 190,806, filed Jul. 10, 2015, the entire contents of all of which are incorporated by reference herein.FIELD OF THE INVENTION[0002]This invention relates, in part, to various compositions and methods for protecting the gastrointestinal microbiome from antibiotic disruption.DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY[0003]The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: SYN-010_Sequencelisting.txt; date recorded: Feb. 22, 2016; file size: 144 KB).BACKGROUND[0004]The gastrointestinal (GI) tract, which houses over one thousand distinct bacterial species and an estimated excess of 1×1014 microorganisms, appears to be central in defining human host health status an...

AI Technical Summary

Benefits of technology

[0009]In some aspects, the present invention is based, in part, on the discovery that one or more antibiotic-degrading agents (e.g. a broad spectrum carbapenemase such as P2A, NDM-1, and KPC-1 / 2) can be formulated to release in one or more locations within the GI tract at which the antibiotic-degrading agent inactivates (e.g. hydrolyzes) an orally or parenterally delivered antibiotic (e.g. a beta lactam antibiotic) and, in doing so, protects the microbiome. However, in some embodiments, the antibiotic-degrading agent does not interfere with intestinal absorption of the antibiotic and, accordingly, does not interfere with systemic blood or plasma levels of the antibiotic. For example, the antibiotic-degrading agent may hydrolyze excess or residual antibiotic that is not absorbed from the GI tract, e.g. after an oral dose, or is returned in active form to the intestinal tract from the systemic circulation, e.g. after an oral or parenteral dose. The invention further identifies the location of such antibiotic-degrading agent release or activation. By way of illustration, in some embodiments, the following two approaches may be employed separately or in combination: utilization of formulations designed to release antibiotic-degrading agent at the desired location in the GI tract and combining the antibiotic with an antibiotic-degrading agent inhibitor. In the latter, in some embodiments, the inhibitor tracks with the antibiotic and serves to protect the antibiotic from the antibiotic-degrading agent. As the concentration of inhibitor decreases, the antibiotic-degrading agent becomes active. Any residual or excess antibiotic that remains in the intestine or reenters with the bile is inactivated prior to encountering the colonic microbiome.

Problems solved by technology

Indeed, antibiotics, often a frontline therapy to prevent deleterious effects of microbes on human health can induce disruption in the microbiome, including in the GI tract, and lead to further disease.

For instance, beta-lactam antibiotics are excreted in the bile, which can damage the colonic microflora and lead to serious illnesses such as Clostridium difficile infection.

However, current therapies target only specific antibiotics and thus there is a need to expand the spectrum of these microbiome-sparing agents.

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