Identification of ADS024, a newly characterized strain of Bacillus velezensis with direct Clostridiodes difficile killing and toxin degradation bio-activities

Abstract

Clostridioides difficile infection (CDI) remains a significant health threat worldwide. C. difficile is an opportunistic, toxigenic pathogen that takes advantage of a disrupted gut microbiome to grow and produce signs and symptoms ranging from diarrhea to pseudomembranous colitis. Antibiotics used to treat C. difficile infection are usually broad spectrum and can further disrupt the commensal gut microbiota, leaving patients susceptible to recurrent C. difficile infection. There is a growing need for therapeutic options that can continue to inhibit the outgrowth of C. difficile after antibiotic treatment is completed. Treatments that degrade C. difficile toxins while having minimal collateral impact on gut bacteria are also needed to prevent recurrence. Therapeutic bacteria capable of producing a range of antimicrobial compounds, proteases, and other bioactive metabolites represent a potentially powerful tool for preventing CDI recurrence following resolution of symptoms. Here, we describe the identification and initial characterization of ADS024 (formerly ART24), a novel therapeutic bacterium that can kill C. difficile in vitro with limited impact on other commensal bacteria. In addition to directly killing C. difficile, ADS024 also produces proteases capable of degrading C. difficile toxins, the drivers of symptoms associated with most cases of CDI. ADS024 is in clinical development for the prevention of CDI recurrence as a single-strain live biotherapeutic product, and this initial data set supports further studies aimed at evaluating ADS024 in future human clinical trials.

ADS024, a Bacillus velezensis strain, protects human colonic epithelial cells against C. difficile toxin-mediated apoptosis

“…Some operational group B. amyloliquefaciens strains produce proteases ( Cho et al, 2003 ; Devaraj et al, 2018 ). ADS024 also possesses toxin-degrading activities ( O’Donnell et al, 2022 ). Therefore, we attempted to characterize the toxin-degrading effects of ADS024 filtrates.…”

“…As described previously, isopropanol (IPA) extracts were prepared from the centrifuged bacterial cells ( O’Donnell et al, 2022 ). IPA extracts are enriched in membrane-bound and internal bacterial metabolites.…”

“…IPA extracts are enriched in membrane-bound and internal bacterial metabolites. Ethyl acetate (EA) extracts from the bacteria-conditioned media of ADS024 and DSM7 were prepared by Adiso Therapeutics as described previously ( O’Donnell et al, 2022 ) and represent enriched samples of bacteria-secreted metabolites. The media without bacteria were made into the control EA extract.…”

“…plantarum ( Fan et al, 2017 ). ADS024 was identified from a large-scale screening of stool samples to detect aerobic spore-forming bacteria with direct anti- C. difficile activity and proteolytic capability ( O’Donnell et al, 2022 ). ADS024 is being investigated as a single-strain live biotherapeutic product (SS-LBP) candidate to prevent CDI recurrence following successful antibacterial treatment.…”

Gut Microbiota and Clostridium difficile: What We Know and the New Frontiers

“…A very promising paper was recently published, in which ADS024, a newly characterized strain of Bacillus velezensis , was identified that appears to have strong activity against C. difficile with negligible impact on the rest of the bacterial flora, and also having protease activity directed against TcdA and TcdB toxins which we have seen to be responsible for the clinical manifestations of this disease [ 73 ].…”