Journal
ANAEROBE
Volume 41, Issue -, Pages 58-67Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.anaerobe.2016.05.015
Keywords
Antibiotic risk factors; Beta-lactamase; Clostridium difficile; Healthcare-associated infections; Microbiome
Categories
Funding
- Synthetic Biologics, Inc.
- SynPhaGen, LLC
- Cosmos ID, Inc.
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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, PIA. Both PIA and SYN-004 were designed as orally delivered, non-systemically available therapeutics for use with intravenous beta-lactam antibiotics. SYN-004 was engineered from PIA, 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. (C) 2016 The Authors. Published by Elsevier Ltd.
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