Next Article in Journal
Improved Positive Predictive Performance of Listeria Indicator Broth: A Sensitive Environmental Screening Test to Identify Presumptively Positive Swab Samples
Next Article in Special Issue
Engineered Lactococcus lactis Secreting IL-23 Receptor-Targeted REX Protein Blockers for Modulation of IL-23/Th17-Mediated Inflammation
Previous Article in Journal
The Chlamydia trachomatis Extrusion Exit Mechanism Is Regulated by Host Abscission Proteins
Previous Article in Special Issue
Microbial Population Changes and Their Relationship with Human Health and Disease
Open AccessArticle

Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage

1
Synthetic Biologics, Inc., 9605 Medical Center Drive, Suite 270, Rockville, MD 20850, USA
2
CosmosID, Inc., Rockville, MD 20850, USA
3
University of Maryland Institute of Advanced Computer Studies, College Park, MD 20740, USA
*
Author to whom correspondence should be addressed.
Microorganisms 2019, 7(5), 150; https://doi.org/10.3390/microorganisms7050150
Received: 6 May 2019 / Revised: 16 May 2019 / Accepted: 23 May 2019 / Published: 27 May 2019
(This article belongs to the Special Issue Gastrointestinal Microbiota Impacts Human Health and Disease)
Antibiotics damage the gut microbiome, which can result in overgrowth of pathogenic microorganisms and emergence of antibiotic resistance. Inactivation of antibiotics in the small intestine represents a novel strategy to protect the colonic microbiota. SYN-004 (ribaxamase) is a beta-lactamase formulated for oral delivery intended to degrade intravenously administered beta-lactam antibiotics in the gastrointestinal (GI) tract. The enteric coating of ribaxamase protects the enzyme from stomach acid and mediates pH-dependent release in the upper small intestine, the site of antibiotic biliary excretion. Clinical benefit was established in animal and human studies in which ribaxamase was shown to degrade ceftriaxone in the GI tract, thereby preserving the gut microbiome, significantly reducing Clostridioides difficile disease, and attenuating antibiotic resistance. To expand ribaxamase utility to oral beta-lactams, delayed release formulations of ribaxamase, SYN-007, were engineered to allow enzyme release in the lower small intestine, distal to the site of oral antibiotic absorption. Based on in vitro dissolution profiles, three SYN-007 formulations were selected for evaluation in a canine model of antibiotic-mediated gut dysbiosis. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were measured after the first and last antibiotic doses and gut microbiomes were evaluated using whole genome shotgun sequence metagenomics analyses of fecal DNA prior to and after antibiotic treatment. Serum amoxicillin levels did not significantly differ +/- SYN-007 after the first dose for all SYN-007 formulations, while only one SYN-007 formulation did not significantly reduce systemic antibiotic concentrations after the last dose. Gut microbiomes of animals receiving amoxicillin alone displayed significant loss of diversity and emergence of antibiotic resistance genes. In contrast, for animals receiving amoxicillin + SYN-007, microbiome diversities were not altered significantly and the presence of antibiotic resistance genes was reduced. These data demonstrate that SYN-007 diminishes amoxicillin-mediated microbiome disruption and mitigates emergence and propagation of antibiotic resistance genes without interfering with antibiotic systemic absorption. Thus, SYN-007 has the potential to protect the gut microbiome by inactivation of beta-lactam antibiotics when administered by both oral and parenteral routes and to reduce emergence of antibiotic-resistant pathogens. View Full-Text
Keywords: beta-lactamase; gut microbiome; antibiotic resistance beta-lactamase; gut microbiome; antibiotic resistance
Show Figures

Figure 1

MDPI and ACS Style

Connelly, S.; Fanelli, B.; Hasan, N.A.; Colwell, R.R.; Kaleko, M. Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage. Microorganisms 2019, 7, 150.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop