Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection
| Autor: | Steven Hubert, John F. Kokai-Kun, Giovanni Widmer, Annie Jones, Todd Parsley, Nur A. Hasan, Sheila Connelly, Perrti Koski, J. Andrew Bristol, Michael Kaleko, Saul Tzipori, Poorani Subramanian, Joseph Sliman |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.drug_class Sus scrofa 030106 microbiology Antibiotics Microbial Sensitivity Tests Drug resistance Antibiotic risk factors Biology Healthcare-associated infections Microbiology beta-Lactamases 03 medical and health sciences Dogs Drug Stability Drug Resistance Bacterial medicine Animals Humans Microbiome Beta-lactamase Enterocolitis Pseudomembranous Gastrointestinal tract Clostridioides difficile Clostridium difficile Hydrogen-Ion Concentration medicine.disease Recombinant Proteins Anti-Bacterial Agents Gastrointestinal Microbiome Kinetics Diarrhea Infectious Diseases Ceftriaxone medicine.symptom Dysbiosis medicine.drug |
| Zdroj: | Anaerobe. 41:58-67 |
| ISSN: | 1075-9964 |
| DOI: | 10.1016/j.anaerobe.2016.05.015 |
| Popis: | The gut microbiome, composed of the microflora that inhabit the gastrointestinal tract and their genomes, make up a complex ecosystem that can be disrupted by antibiotic use. The ensuing dysbiosis is conducive to the emergence of opportunistic pathogens such as Clostridium difficile. A novel approach to protect the microbiome from antibiotic-mediated dysbiosis is the use of beta-lactamase enzymes to degrade residual antibiotics in the gastrointestinal tract before the microflora are harmed. Here we present the preclinical development and early clinical studies of the beta-lactamase enzymes, P3A, currently referred to as SYN-004, and its precursor, P1A. Both P1A and SYN-004 were designed as orally-delivered, non-systemically available therapeutics for use with intravenous beta-lactam antibiotics. SYN-004 was engineered from P1A, a beta-lactamase isolated from Bacillus licheniformis, to broaden its antibiotic degradation profile. SYN-004 efficiently hydrolyses penicillins and cephalosporins, the most widely used IV beta-lactam antibiotics. In animal studies, SYN-004 degraded ceftriaxone in the GI tract of dogs and protected the microbiome of pigs from ceftriaxone-induced changes. Phase I clinical studies demonstrated SYN-004 safety and tolerability. Phase 2 studies are in progress to assess the utility of SYN-004 for the prevention of antibiotic-associated diarrhea and Clostridium difficile disease. |
| Databáze: | OpenAIRE |
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