Oral metallo-beta-lactamase protects the gut microbiome from carbapenem-mediated damage and reduces propagation of antibiotic resistance in pigs

Abstract

Antibiotics can damage the gut microbiome, leading to serious adventitious infections and emergence of antibiotic resistant pathogens. Antibiotic inactivation in the GI tract represents a strategy to protect colonic microbiota integrity and reduce antibiotic resistance. Clinical utility of this approach was established when SYN-004 (ribaxamase), an orally-administered beta-lactamase, was demonstrated to degrade ceftriaxone in the GI tract and preserve the gut microbiome. Ribaxamase degrades penicillins and cephalosporin beta-lactams, but not carbapenems. To expand this prophylactic approach to include all classes of beta-lactam antibiotics, a novel carbapenemase, formulated for oral administration, SYN-006, was evaluated in a porcine model of antibiotic-mediated gut dysbiosis. Pigs (20 kg, n = 16) were treated with the carbapenem, ertapenem (ERT), (IV, 30 mg/kg, SID) for 4 days and a cohort (n = 8) also received SYN-006 (PO, 50 mg, QID), beginning the day before antibiotic administration. ERT serum levels were not statistically different in ERT and ERT + SYN-006 groups, indicating that SYN-006 did not alter systemic antibiotic levels. Microbiomes were evaluated using whole genome shotgun metagenomics analyses of fecal DNA collected prior to and after antibiotic treatment. ERT caused significant changes to the gut microbiome that were mitigated in the presence of SYN-006. In addition, SYN-006 attenuated emergence of antibiotic resistance, including encoded beta-lactamases and genes conferring resistance to a broad range of antibiotics such as aminoglycosides and macrolides. SYN-006 has the potential to become the first therapy designed to protect the gut microbiome from all classes of beta-lactam antibiotics and reduce emergence of carbapenem-resistant pathogens.