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.

Novel rifamycins (new chemical entities [NCEs]) having MICs of 0.002 to 0.03 g/ml against Staphylococcus aureus and retaining some activity against rifampin-resistant mutants were tested for in vivo efficacy against susceptible and rifampin-resistant strains of S. aureus. Rifalazil and rifampin had a 50% effective dose (ED 50 ) of 0.06 mg/kg of body weight when administered as a single intravenous (i.v.) dose in a murine septicemia model against a susceptible strain of S. aureus. The majority of NCEs showed efficacy at a lower i.v. dose (0.003 to 0.06 mg/kg). In addition, half of the NCEs tested for oral efficacy had ED 50 s in the range of 0.015 to 0.13 mg/kg, i.e., lower or equivalent to the oral ED 50 s of rifampin and rifalazil. NCEs were also tested in the septicemia model against a rifampin-resistant strain of S. aureus. Twenty-four of 169 NCEs were efficacious when administered as a single oral dose of 80 mg/kg. These NCEs were examined in the murine thigh infection model against a susceptible strain of S. aureus. Several NCEs dosed by intraperitoneal injection at 0.06 mg/kg caused a significant difference in bacterial titer compared with placebo-treated animals. No NCEs showed efficacy in the thigh model against a highly rifampin-resistant strain. However, several NCEs showed an effect when tested against a partially rifampin-resistant strain. The NCEs having a 25-hydroxyl moiety were more effective as a group than their 25-O-acetyl counterparts. These model systems defined candidate NCEs as components of potential combination therapies to treat systemic infections or as monotherapeutic agents for topical applications.Rifalazil [3Ј-hydroxy-5Ј-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin], also referred to as KRM-1648 or ABI-1648, is a rifamycin derivative with exceptionally low MICs against gram-positive bacteria (7,19), Helicobacter pylori (1), and Chlamydia (9,18,21,22). The potency of rifalazil and the other rifamycins derives from their specific inhibition of bacterial RNA polymerase (6). Preclinical animal studies suggest that rifalazil has efficacy against Chlamydia pneumoniae (9), Clostridium difficile (2), Mycobacterium tuberculosis (8,19,20), and Staphylococcus aureus (7). In addition, rifalazil has been tested in phase 2 human clinical trials for the treatment of tuberculosis (5) L-992b, 2004). One of the attributes of rifamycins, including rifalazil, is the propensity for resistance to develop as a result of the occurrence of mutations in the rpoB gene. These mutations cause modifications in the binding site of the target enzyme, the ␤ subunit of RNA polymerase, in pathogens such as M. tuberculosis (13, 17, 25, 26), S. aureus (23, 24), and Streptococcus pyogenes (3). Thus, rifamycins have been confined primarily to multiple-drug therapy where resistance development is less of an issue.Recently, we described a collection of over 700 novel rifamycins which are related in structure to rifalazil. More than 50% of these new chemical entities (NCEs) are more active against gram-positive bacteri...

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