Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection.
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.
Synthetic Biologics, Inc., Rockville, MD, USA. Electronic address: mkaleko@syntheticbiologics.com.
Michael
M
Kaleko
Synthetic Biologics, Inc., Rockville, MD, USA.
J Andrew
JA
Bristol
Synthetic Biologics, Inc., Rockville, MD, USA.
Steven
S
Hubert
SynPhaGen, LLC, Rockville, MD, USA.
Todd
T
Parsley
Tufts Cummings School of Veterinary Medicine, North Grafton, MA, USA.
Giovanni
G
Widmer
Tufts Cummings School of Veterinary Medicine, North Grafton, MA, USA.
Saul
S
Tzipori
CosmosID, Inc., Rockville, MD, USA.
Poorani
P
Subramanian
CosmosID, Inc., Rockville, MD, USA.
Nur
N
Hasan
Ipsat Therapies, Helsinki, Finland (closed 2011).
Perrti
P
Koski
Synthetic Biologics, Inc., Rockville, MD, USA.
John
J
Kokai-Kun
Synthetic Biologics, Inc., Rockville, MD, USA.
Joseph
J
Sliman
Synthetic Biologics, Inc., Rockville, MD, USA.
Annie
A
Jones
Synthetic Biologics, Inc., Rockville, MD, USA.
Sheila
S
Connelly
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016360:Clostridioides difficile / Q000187:drug effects; D004285:Dogs; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D004761:Enterocolitis, Pseudomembranous / Q000517:prevention & control*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D034421:Sus scrofa; D001618:beta-Lactamases / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D011994:Recombinant Proteins; C000613271:SYN-004; D001618:beta-Lactamases
Antibiotic risk factors; Beta-lactamase; Clostridium difficile; Healthcare-associated infections; Microbiome