Abstract

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.

Highlights

  • The gut microbiome, composed of the commensal microbiota and their genetic material, represents a complex ecosystem important to human health

  • Ribaxamase, derived from a class A serine beta-lactamase, is sensitive to beta-lactamase inhibitors in vitro [23], but was capable of protecting the gut microbiome from antibiotic-mediated damage when delivered with amoxicillin/clavulanate in dogs

  • The ribaxamase precursor, P1A beta-lactamase, was effective in the presence of beta-lactamase inhibitors in humans treated with clavulanate, to protect the gut microbiome from oral amoxicillin/clavulanate without interfering with oral amoxicillin systemic absorption

Read more

Summary

Introduction

The gut microbiome, composed of the commensal microbiota and their genetic material, represents a complex ecosystem important to human health. Antibiotics disrupt this bionetwork, resulting in alterations of the normal microbial balance that can weaken colonization resistance and result in pathobiont overgrowth. The gut microbiome functions as a reservoir of antibiotic resistance [6]. Selective pressure caused by antimicrobial use promotes the emergence and evolution of pathogens by accelerating the transfer of antibiotic resistance genes [6,7]. Limiting the exposure of the gut microbiota to antimicrobials by their inactivation in the gastrointestinal (GI) tract is a strategy to preserve the gut microbiome and reduce antibiotic resistance

Results
Discussion
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.