Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota

Antimicrob Agents Chemother. 2019 Dec 20;64(1):e01395-19. doi: 10.1128/AAC.01395-19. Print 2019 Dec 20.


CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 μg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at under identifier NCT02106338.).

Keywords: CRS3123; Clostridioides difficile; MAD study; antibiotic; gut microbiota; microbiome; narrow spectrum; phase 1; sporulation; toxin production.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / adverse effects
  • Anti-Bacterial Agents / pharmacokinetics
  • Benzopyrans / administration & dosage*
  • Benzopyrans / adverse effects
  • Benzopyrans / pharmacokinetics
  • Clostridioides difficile / drug effects*
  • Clostridioides difficile / enzymology
  • Clostridioides difficile / genetics
  • Clostridium Infections / drug therapy
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Electrocardiography
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Gastrointestinal Microbiome / drug effects*
  • Healthy Volunteers
  • Humans
  • Male
  • Methionine-tRNA Ligase / antagonists & inhibitors
  • Methionine-tRNA Ligase / genetics
  • Microbial Sensitivity Tests
  • Middle Aged
  • Thiophenes / administration & dosage*
  • Thiophenes / adverse effects
  • Thiophenes / pharmacokinetics
  • Young Adult


  • Anti-Bacterial Agents
  • Benzopyrans
  • Enzyme Inhibitors
  • REP 3123
  • Thiophenes
  • Methionine-tRNA Ligase

Associated data