{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T23:32:52Z","timestamp":1790465572884,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T00:00:00Z","timestamp":1579651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>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) +\/\u2122 SYN-007 (10 mg, PO, TID) for five days. Serum amoxicillin levels were not significantly different +\/\u2122 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.<\/jats:p>","DOI":"10.3390\/microorganisms8020152","type":"journal-article","created":{"date-parts":[[2020,1,22]],"date-time":"2020-01-22T11:17:57Z","timestamp":1579691877000},"page":"152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"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"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0951-3593","authenticated-orcid":false,"given":"Sheila","family":"Connelly","sequence":"first","affiliation":[{"name":"Synthetic Biologics, Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Fanelli","sequence":"additional","affiliation":[{"name":"CosmosID, Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur A.","family":"Hasan","sequence":"additional","affiliation":[{"name":"CosmosID, Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5432-1502","authenticated-orcid":false,"given":"Rita R.","family":"Colwell","sequence":"additional","affiliation":[{"name":"CosmosID, Inc., Rockville, MD 20850, USA"},{"name":"College of Computer, Mathematical, &amp; Natural Sciences, University of Maryland Institute of Advanced Computer Studies, College Park, MD 20742, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kaleko","sequence":"additional","affiliation":[{"name":"Synthetic Biologics, Inc., Rockville, MD 20850, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Knecht, H., Neulinger, S.C., Heinsen, F.A., Knecht, C., Schilhabel, A., Schmitz, R.A., Zimmermann, A., dos Santos, V.M., Ferrer, M., and Rosenstiel, P.C. (2014). Effects of beta-lactam antibiotics and fluoroquinolones on human gut microbiota in relation to Clostridium difficile associated diarrhea. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0089417"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccc.2010.11.004","article-title":"Pharmacodynamic Approaches to Optimizing Beta-Lactam Therapy","volume":"27","author":"Crandon","year":"2011","journal-title":"Crit. Care Clin."},{"key":"ref_3","first-page":"649","article-title":"Elaboration of a consensual definition of de-escalation allowing a ranking of beta-lactams","volume":"21","author":"Weiss","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijantimicag.2016.03.008","article-title":"Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: A systematic review and meta-analysis","volume":"48","author":"Vardakas","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1093\/cid\/cix1112","article-title":"Evaluating the Risk Factors for Hospital-Onset Clostridium difficile Infections in a Large Healthcare System","volume":"66","author":"Watson","year":"2018","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3389\/fmicb.2013.00087","article-title":"The human microbiome as a reservoir of antimicrobial resistance","volume":"4","author":"Penders","year":"2013","journal-title":"Front. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/nrmicro2989","article-title":"\u2019Blooming\u2019 in the gut: How dysbiosis might contribute to pathogen evolution","volume":"11","author":"Stecher","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.ijpharm.2017.10.001","article-title":"Formulation development of SYN-004 (ribaxamase) oral solid dosage form, a beta-lactamase to prevent intravenous antibiotic-associated dysbiosis of the colon","volume":"534","author":"Bristol","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/jam.13432","article-title":"SYN-004 (ribaxamase), an Oral Beta-Lactamase, Mitigates Antibiotic-Mediated Dysbiosis in a Porcine Gut Microbiome Model","volume":"123","author":"Connelly","year":"2017","journal-title":"J. Appl. Microbiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kokai-Kun, J., and Connelly, S. (2019). Ribaxamase, an orally administered \u03b2-lactamase, protects the gut microbiome in patients treated with ceftriaxone. J. Transl. Sci., 6.","DOI":"10.15761\/JTS.1000344"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kokai-Kun, J.F., Roberts, T., Coughlin, O., Sicard, E., Rufiange, M., Fedorak, R., Carter, C., Adams, M.H., Longstreth, J., and Whalen, H. (2017). The oral beta-lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies. Antimicrob. Agents Chemother., 61.","DOI":"10.1128\/AAC.02197-16"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S1473-3099(18)30731-X","article-title":"Use of ribaxamase (SYN-004), a \u03b2-lactamase, to prevent Clostridium difficile infection in \u03b2-lactam-treated patients: A double-blind, phase 2b, randomised placebo-controlled trial","volume":"19","author":"Roberts","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_13","unstructured":"Centers for Disease Control and Prevention (2016). Outpatient Antibiotic Prescriptions United States, Centers for Disease Control and Prevention."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"477","DOI":"10.3934\/publichealth.2019.4.477","article-title":"Low dose oral beta-lactamase protects the gut microbiome from oral beta-lactam-mediated damage in dogs","volume":"6","author":"Connelly","year":"2019","journal-title":"AIMS Public Health"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Connelly, S., Fanelli, B., Hasan, N.A., Colwell, R.R., and Kaleko, M. (2019). Oral Beta-Lactamase Protects the Canine Gut Microbiome from Oral Amoxicillin-Mediated Damage. Microorganisms, 7.","DOI":"10.3390\/microorganisms7050150"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/clpt.1994.138","article-title":"Differential absorption of amoxicillin from the human small and large intestine","volume":"56","author":"Barr","year":"1994","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.xphs.2017.09.028","article-title":"Development of a Modified-Release Formulation of Lovastatin Targeted to Intestinal Methanogens Implicated in Irritable Bowel Syndrome With Constipation","volume":"107","author":"Hubert","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_18","first-page":"90","article-title":"Reported Rates of Diarrhea Following Oral Penicillin Therapy in Pediatric Clinical Trials","volume":"20","author":"Kuehn","year":"2015","journal-title":"J. Pediatr. Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/j.1538-7305.1948.tb01338.x","article-title":"A mathematical theory of communication","volume":"27","author":"Shannon","year":"1948","journal-title":"Bell Syst. Tech. J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gaujoux, R., and Seoighe, C. (2010). A flexible R package for nonnegative matrix factorization. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-367"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e02100","DOI":"10.1002\/ecs2.2100","article-title":"How robust are popular beta diversity indices to sampling error?","volume":"9","author":"Schroeder","year":"2018","journal-title":"Ecosphere"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1182\/blood-2014-02-554725","article-title":"The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation","volume":"124","author":"Taur","year":"2014","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.anaerobe.2016.05.015","article-title":"Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection","volume":"41","author":"Kaleko","year":"2016","journal-title":"Anaerobe"},{"key":"ref_24","first-page":"838","article-title":"IPSAT P1A, a class A beta-lactamase therapy for the prevention of penicillin-induced disruption to the intestinal microflora","volume":"10","author":"Pitout","year":"2009","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Hoberman, A., Paradise, J.L., Rockette, H.E., Jeong, J.H., Kearney, D.H., Bhatnagar, S., Shope, T.R., Mu\u00f1iz, G., Martin, J.M., and Kurs-Lasky, M. (2017). Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media. Antimicrob. Agents Chemother., 61.","DOI":"10.1128\/AAC.00238-17"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Bulow, C., Langdon, A., Hink, T., Wallace, M., Reske, K.A., Patel, S., Sun, X., Seiler, S., Jones, S., and Kwon, J.H. (2018). Impact of Amoxicillin-Clavulanate followed by Autologous Fecal Microbiota Transplantation on Fecal Microbiome Structure and Metabolic Potential. mSphere, 3.","DOI":"10.1128\/mSphereDirect.00588-18"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1080\/19490976.2016.1267890","article-title":"Prospective randomized controlled study on the effects of Saccharomyces boulardii CNCM I-745 and amoxicillin-clavulanate or the combination on the gut microbiota of healthy volunteers","volume":"8","author":"Kabbani","year":"2017","journal-title":"Gut Microbes"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1046\/j.1365-2672.2000.00774.x","article-title":"A Fusobacterium mortiferum strain produces a bacteriocin-like substance(s) inhibiting Salmonella enteritidis","volume":"31","author":"Portrait","year":"2000","journal-title":"Lett. Appl. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1128\/CMR.14.4.933-951.2001","article-title":"Extended-spectrum beta-lactamases in the 21st century: Characterization, epidemiology, and detection of this important resistance threat","volume":"14","author":"Bradford","year":"2001","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1574-6941.2009.00808.x","article-title":"Changes in fecal microbiota of healthy dogs administered amoxicillin","volume":"71","author":"Skancke","year":"2010","journal-title":"FEMS Microbiol. Ecol."},{"key":"ref_31","first-page":"3305","article-title":"Routine antibiotic therapy in dogs increases the detection of antimicrobial-resistant faecal Escherichia coli","volume":"73","author":"Schmidt","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.anaerobe.2018.04.012","article-title":"Distinct consequences of amoxicillin and ertapenem exposure in the porcine gut microbiome","volume":"53","author":"Connelly","year":"2018","journal-title":"Anaerobe"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1073\/pnas.1120238109","article-title":"In-feed antibiotic effects on the swine intestinal microbiome","volume":"109","author":"Looft","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/2\/152\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:30:17Z","timestamp":1760362217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/8\/2\/152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,22]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["microorganisms8020152"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms8020152","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,22]]}}}