Cargando…

SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs

Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intr...

Descripción completa

Detalles Bibliográficos
Autores principales: Connelly, Sheila, Fanelli, Brian, Hasan, Nur A., Colwell, Rita R., Kaleko, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074739/
https://www.ncbi.nlm.nih.gov/pubmed/31979034
http://dx.doi.org/10.3390/microorganisms8020152
_version_ 1783506902553985024
author Connelly, Sheila
Fanelli, Brian
Hasan, Nur A.
Colwell, Rita R.
Kaleko, Michael
author_facet Connelly, Sheila
Fanelli, Brian
Hasan, Nur A.
Colwell, Rita R.
Kaleko, Michael
author_sort Connelly, Sheila
collection PubMed
description Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioides difficile disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibitor, was investigated. Dogs received amoxicillin (40 mg/kg, orally (PO), three times a day (TID)) or the combined antibiotic/beta-lactamase inhibitor, amoxicillin/clavulanate (40 mg/kg amoxicillin, 5.7 mg/kg clavulanate, PO, TID) +/™ SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +/™ SYN-007 compared to amoxicillin alone or amoxicillin/clavulanate alone as controls for both first and last doses, indicating SYN-007 did not interfere with systemic absorption of the antibiotic. Whole genome shotgun metagenomics analyses of the fecal microbiomes demonstrated both amoxicillin and amoxicillin/clavulanate significantly reduced diversity and increased the frequency of antibiotic resistance genes. Microbiome damage appeared more severe with amoxicillin/clavulanate. In contrast, with SYN-007, microbiome diversity was not significantly altered, and frequency of antibiotic resistance genes did not increase. Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically.
format Online
Article
Text
id pubmed-7074739
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-70747392020-03-20 SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs Connelly, Sheila Fanelli, Brian Hasan, Nur A. Colwell, Rita R. Kaleko, Michael Microorganisms Article Beta-lactamases, enzymes produced by bacteria to degrade beta-lactam antibiotics, have been harnessed as therapeutics to protect the gut microbiome from damage caused by antibiotics. Proof-of-concept of this approach using SYN-004 (ribaxamase), a beta-lactamase formulated for oral delivery with intravenous (IV) penicillins and cephalosporins, was demonstrated with animal models and in humans. Ribaxamase degraded ceftriaxone in the gastrointestinal tract, protected the gut microbiome, significantly reduced the incidence of Clostridioides difficile disease and attenuated emergence of antibiotic resistant organisms. SYN-007 is a delayed release formulation of ribaxamase intended for use with oral beta-lactams. In dogs treated with oral amoxicillin, SYN-007 diminished antibiotic-mediated microbiome disruption and reduced the emergence of antibiotic resistance without altering amoxicillin systemic absorption. Here, SYN-007 function in the presence of clavulanate, a beta-lactamase inhibitor, was investigated. Dogs received amoxicillin (40 mg/kg, orally (PO), three times a day (TID)) or the combined antibiotic/beta-lactamase inhibitor, amoxicillin/clavulanate (40 mg/kg amoxicillin, 5.7 mg/kg clavulanate, PO, TID) +/™ SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +/™ SYN-007 compared to amoxicillin alone or amoxicillin/clavulanate alone as controls for both first and last doses, indicating SYN-007 did not interfere with systemic absorption of the antibiotic. Whole genome shotgun metagenomics analyses of the fecal microbiomes demonstrated both amoxicillin and amoxicillin/clavulanate significantly reduced diversity and increased the frequency of antibiotic resistance genes. Microbiome damage appeared more severe with amoxicillin/clavulanate. In contrast, with SYN-007, microbiome diversity was not significantly altered, and frequency of antibiotic resistance genes did not increase. Importantly, SYN-007 functioned in the presence of clavulanate to protect the gut microbiome indicating that SYN-007 activity was not inhibited by clavulanate in the dog gastrointestinal tract. SYN-007 has the potential to expand microbiome protection to beta-lactam/beta-lactamase inhibitor combinations delivered orally or systemically. MDPI 2020-01-22 /pmc/articles/PMC7074739/ /pubmed/31979034 http://dx.doi.org/10.3390/microorganisms8020152 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Connelly, Sheila
Fanelli, Brian
Hasan, Nur A.
Colwell, Rita R.
Kaleko, Michael
SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs
title SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs
title_full SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs
title_fullStr SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs
title_full_unstemmed SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs
title_short SYN-007, an Orally Administered Beta-Lactamase Enzyme, Protects the Gut Microbiome from Oral Amoxicillin/Clavulanate without Adversely Affecting Antibiotic Systemic Absorption in Dogs
title_sort syn-007, an orally administered beta-lactamase enzyme, protects the gut microbiome from oral amoxicillin/clavulanate without adversely affecting antibiotic systemic absorption in dogs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074739/
https://www.ncbi.nlm.nih.gov/pubmed/31979034
http://dx.doi.org/10.3390/microorganisms8020152
work_keys_str_mv AT connellysheila syn007anorallyadministeredbetalactamaseenzymeprotectsthegutmicrobiomefromoralamoxicillinclavulanatewithoutadverselyaffectingantibioticsystemicabsorptionindogs
AT fanellibrian syn007anorallyadministeredbetalactamaseenzymeprotectsthegutmicrobiomefromoralamoxicillinclavulanatewithoutadverselyaffectingantibioticsystemicabsorptionindogs
AT hasannura syn007anorallyadministeredbetalactamaseenzymeprotectsthegutmicrobiomefromoralamoxicillinclavulanatewithoutadverselyaffectingantibioticsystemicabsorptionindogs
AT colwellritar syn007anorallyadministeredbetalactamaseenzymeprotectsthegutmicrobiomefromoralamoxicillinclavulanatewithoutadverselyaffectingantibioticsystemicabsorptionindogs
AT kalekomichael syn007anorallyadministeredbetalactamaseenzymeprotectsthegutmicrobiomefromoralamoxicillinclavulanatewithoutadverselyaffectingantibioticsystemicabsorptionindogs