Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection

Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Kaleko, M., Bristol, J., A., Hubert, S., Parsley, T., Widmer, G., Tzipori, S., Subramanian, P., Hasan, N., Koski, P., Kokai-Kun, J., Sliman, J., Jones, A., & Connelly, S. Anaerobe, 41:58-67, Academic Press, 10, 2016.

Paper doi abstract bibtex

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.

@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},
 type = {article},
 year = {2016},
 keywords = {Antibiotic risk factors,Beta-lactamase,Clostridium difficile,Healthcare-associated infections,Microbiome},
 pages = {58-67},
 volume = {41},
 month = {10},
 publisher = {Academic Press},
 day = {1},
 id = {ced4f73b-5c2e-32e0-88bc-5634ff4c9a1c},
 created = {2025-10-30T12:26:02.077Z},
 accessed = {2025-10-30},
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 last_modified = {2025-10-30T12:26:06.285Z},
 read = {false},
 starred = {false},
 authored = {false},
 confirmed = {false},
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 abstract = {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.},
 bibtype = {article},
 author = {Kaleko, Michael and Bristol, J. Andrew and Hubert, Steven and Parsley, Todd and Widmer, Giovanni and Tzipori, Saul and Subramanian, Poorani and Hasan, Nur and Koski, Perrti and Kokai-Kun, John and Sliman, Joseph and Jones, Annie and Connelly, Sheila},
 doi = {10.1016/J.ANAEROBE.2016.05.015},
 journal = {Anaerobe}
}

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