Compositions comprising recombinant probiotic bacteria and methods of use thereof
Inventors
VEDANTAM, Gayatri • VISWANATHAN, Virinchipuram K. • MALLOZZI, Michael
Assignees
US Department of Veterans Affairs • University of Arizona
Publication Number
US-10583186-B2
Publication Date
2020-03-10
Expiration Date
2036-01-22
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Abstract
The invention features probiotic bacteria expressing Clostridium difficile SlpA, or fragment thereof, and its use for the treatment or prevention of Clostridium difficile infection and gut colonization.
Core Innovation
The invention provides probiotic bacteria expressing Clostridium difficile surface protein SlpA, or fragment or chimera thereof, and their use for treating or preventing Clostridium difficile infection and gut colonization. The probiotic bacteria include Lactococcus lactis and Lactobacillus acidophilus, engineered to express chimeric SlpA polypeptides comprising a bacterial secretion signal, C. difficile SlpA variable domain, and Lactobacillus SlpA cell wall binding domain.
The problem addressed is the lack of effective treatments and preventatives for Clostridium difficile infection (CDI) and colonization. CDI is a leading cause of antibiotic-associated diarrhea in humans and animals and is exacerbated by antibiotic use that suppresses protective gut microbiota. Current treatments with antibiotics can alter gut bacterial composition, and while vaccines are being developed, they do not protect against C. difficile colonization, creating an urgent need for novel therapeutic methods.
Claims Coverage
The patent includes multiple independent claims relating to isolated polypeptides with specific domain organization and sequences.
Isolated chimeric SlpA polypeptide composition
Describes an isolated polypeptide comprising, from amino-terminus to carboxy-terminus, a bacterial secretion signal, a C. difficile SlpA variable domain, and a Lactobacillus SlpA cell wall binding domain with the amino acid sequence SEQ ID NO:2.
Polypeptide with defined secretion signal and domains
Covers an isolated polypeptide comprising a bacterial secretion signal having the amino acid sequence SEQ ID NO: 3, a C. difficile SlpA variable domain, and a Lactobacillus SlpA cell wall binding domain.
Isolated polypeptide having the complete defined sequence
Claims an isolated polypeptide having the amino acid sequence SEQ ID NO: 4, which includes a bacterial secretion signal, C. difficile SlpA variable domain, and a Lactobacillus SlpA cell wall binding domain.
The independent claims focus on isolated chimeric SlpA polypeptides comprising a bacterial secretion signal, a C. difficile SlpA variable domain, and a Lactobacillus SlpA cell wall binding domain, with specific amino acid sequences defining these components.
Stated Advantages
The recombinant probiotic bacteria expressing chimeric SlpA effectively colonize the gut, competing with Clostridium difficile and protecting against virulent C. difficile challenge.
The invention provides a novel treatment or preventative approach for Clostridium difficile infection and colonization that avoids the use of antibiotics and their associated microbiome disruption.
Integration of nucleic acid sequences encoding chimeric SlpA into probiotic bacteria chromosomes ensures stable SlpA expression and biocontainment through auxotrophic control, enhancing safety and efficacy for clinical use.
Documented Applications
Treatment or prevention of Clostridium difficile infection and colonization in humans and animals, including those undergoing or having undergone antibiotic treatment.
Colonization of the gut or digestive tract of a subject with recombinant Lactococcus or Lactobacillus bacteria expressing chimeric SlpA polypeptides.
Use of probiotic bacteria expressing chimeric SlpA for replacing a gut microbiome associated with disease.
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