Dataset Information

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.

SUBMITTER: Connelly S

PROVIDER: S-EPMC6370672 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Oral Metallo-Beta-Lactamase Protects the Gut Microbiome From Carbapenem-Mediated Damage and Reduces Propagation of Antibiotic Resistance in Pigs.

Connelly Sheila S Fanelli Brian B Hasan Nur A NA Colwell Rita R RR Kaleko Michael M

Frontiers in microbiology 20190205

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 peni ...[more]

PMID: 30804903

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Project description: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.

Project description:Production of metallo-β-lactamases (MBLs), which hydrolyze carbapenems, is a cause of carbapenem resistance in Enterobacteriaceae Development of effective inhibitors for MBLs is one approach to restore carbapenem efficacy in carbapenem-resistant Enterobacteriaceae (CRE). We report here that sulfamoyl heteroarylcarboxylic acids (SHCs) can competitively inhibit the globally spreading and clinically relevant MBLs (i.e., IMP-, NDM-, and VIM-type MBLs) at nanomolar to micromolar orders of magnitude. Addition of SHCs restored meropenem efficacy against 17/19 IMP-type and 7/14 NDM-type MBL-producing Enterobacteriaceae to satisfactory clinical levels. SHCs were also effective against IMP-type MBL-producing Acinetobacter spp. and engineered Escherichia coli strains overproducing individual minor MBLs (i.e., TMB-2, SPM-1, DIM-1, SIM-1, and KHM-1). However, SHCs were less effective against MBL-producing Pseudomonas aeruginosa Combination therapy with meropenem and SHCs successfully cured mice infected with IMP-1-producing E. coli and dually NDM-1/VIM-1-producing Klebsiella pneumoniae clinical isolates. X-ray crystallographic analyses revealed the inhibition mode of SHCs against MBLs; the sulfamoyl group of SHCs coordinated to two zinc ions, and the carboxylate group coordinated to one zinc ion and bound to positively charged amino acids Lys224/Arg228 conserved in MBLs. Preclinical testing revealed that the SHCs showed low toxicity in cell lines and mice and high stability in human liver microsomes. Our results indicate that SHCs are promising lead compounds for inhibitors of MBLs to combat MBL-producing CRE.IMPORTANCE Carbapenem antibiotics are the last resort for control of severe infectious diseases, bloodstream infections, and pneumonia caused by Gram-negative bacteria, including Enterobacteriaceae However, carbapenem-resistant Enterobacteriaceae (CRE) strains have spread globally and are a critical concern in clinical settings because CRE infections are recognized as a leading cause of increased mortality among hospitalized patients. Most CRE produce certain kinds of serine carbapenemases (e.g., KPC- and GES-type β-lactamases) or metallo-β-lactamases (MBLs), which can hydrolyze carbapenems. Although effective MBL inhibitors are expected to restore carbapenem efficacy against MBL-producing CRE, no MBL inhibitor is currently clinically available. Here, we synthesized 2,5-diethyl-1-methyl-4-sulfamoylpyrrole-3-carboxylic acid (SPC), which is a potent inhibitor of MBLs. SPC is a remarkable lead compound for clinically useful MBL inhibitors and can potentially provide a considerable benefit to patients receiving treatment for lethal infectious diseases caused by MBL-producing CRE.

Project description:Antibiotics, while lifesaving, damage the gut microbiome and can precipitate proliferation of pathobionts. A strategy to preserve gut microbiome integrity is to eliminate biologically active antimicrobials excreted into the gastrointestinal tract (GI) without negatively affecting antibiotic therapeutic efficacy. Clinical proof of concept was achieved with SYN-004 (ribaxamase), a beta-lactamase enzyme formulated for oral delivery with intravenous penicillins and cephalosporins. Ribaxamase inactivated intestinal ceftriaxone, protected the gut microbiome, and significantly reduced the incidence of Clostridioides difficile disease. For use with oral beta-lactam antibiotics, a delayed release formulation of ribaxamase, SYN-007, was engineered for dissolution in the lower small intestine distal to the site of oral antibiotic absorption. In dogs that received oral amoxicillin, SYN-007 reduced microbiome disruption without interfering with amoxicillin systemic absorption. Here, a study to determine the lowest effective dose of SYN-007 was performed. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (PO, TID) at three doses, 10 mg, 3 mg, or 1 mg for five days. Serum amoxicillin levels, measured after the first and last antibiotic doses, were not significantly different +/-SYN-007 at all dose levels indicating that SYN-007 did not interfere with amoxicillin systemic absorption. Microbiome analyses demonstrated that amoxicillin significantly reduced bacteria richness and microbiome diversity resulting in altered microbiome composition. However, with all doses of SYN-007, microbiome richness and diversity were not significantly different from pretreatment and changes in microbiome composition were attenuated. These data demonstrate that effective SYN-007 doses can be reduced at least 10-fold while maintaining gut microbiome preservation. The potential to employ low SYN-007 doses to protect the gut microbiota has important implications for enhancing therapeutic outcomes for patients receiving oral beta-lactam antibiotics while simultaneously reducing cost per dose and ultimately, healthcare expenses.

Dataset Information

Oral Metallo-Beta-Lactamase Protects the Gut Microbiome From Carbapenem-Mediated Damage and Reduces Propagation of Antibiotic Resistance in Pigs.

Publications

Oral Metallo-Beta-Lactamase Protects the Gut Microbiome From Carbapenem-Mediated Damage and Reduces Propagation of Antibiotic Resistance in Pigs.

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