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

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.

Shotgun metagenomics unravels higher antibiotic resistome profile in Bangladeshi gut microbiome

“…Analyzing the human gut resistome is critical to decrypt the spreading of ARGs and their types or prevalence (35). ARGs in non-pathogenic microorganisms are not a threat and sometimes protective for the microbiome against antibiotics, however, these genes can be obtained by pathogenic bacteria through mechanisms such as DNA conjugation, transformation, and transduction (33,36). These processes transmit viral (bacteriophage) elements and mobilomes like plasmids.…”

New Approaches to Manage Infections in Transplant Recipients: Report From the 2023 GTI (Infection and Transplantation Group) Annual Meeting

“…For example, ribaxamase (an orally administered beta-lactamase hydrolyzing β-lactams in the colon appears promising in Phase 2 studies although limited to β-lactam antibiotics) and DAV-132 which is a millimetric beads consisting of a core of a specific activated charcoal surrounded by a polymer coating that is insoluble during transit. The charcoal is activated in the ileum and adsorbs and thereby inactivates antibiotics in the caecum/colon [12][13][14][15][16]. For now, no investigation of this strategy exist in transplant recipients but its evaluation and implementation are of interest in the TOS patients, a population highly exposed to antibiotics.…”

Dynamic Effect of β-Lactam Antibiotic Inactivation Due to the Inter- and Intraspecies Interaction of Drug-Resistant Microbes

“…19−22 Conceptualized approaches to β-lactamase administration were shown to impart changes to the gut resistome through antibiotic inactivation. 23,24 These studies emphasized the potential of the inactivation of β-lactam antibiotics to protect the gut microbiome in the gastro- intestinal tract (GI) tract. However, the role of β-lactamases on various organisms is not fully understood due to the lack of model systems that can facilitate the evaluation of specific organisms' interaction in a dynamic manner.…”

“…The β-lactam class of antibiotics encompasses a broad spectrum of antimicrobials, including ampicillin, penicillin, and cephalosporins, comprising 65% of the world market for antibiotics . To date, β-lactamases have been considered as one of the major mechanisms of resistance in the fight against β-lactam class of antibiotics by acting on the bacterial cell wall synthesis. , This mechanism of resistance is even more common in microorganisms that reside in the human gut and play a protective role in minimizing the damage caused by antibiotics. − Conceptualized approaches to β-lactamase administration were shown to impart changes to the gut resistome through antibiotic inactivation. , These studies emphasized the potential of the inactivation of β-lactam antibiotics to protect the gut microbiome in the gastrointestinal tract (GI) tract. However, the role of β-lactamases on various organisms is not fully understood due to the lack of model systems that can facilitate the evaluation of specific organisms’ interaction in a dynamic manner.…”