2. Academic Validation
  3. Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408

Enhancing the therapeutic window for Spectinamide anti-tuberculosis Agents: Synthesis, Evaluation, and activation of phosphate prodrug 3408

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129934. doi: 10.1016/j.bmcl.2024.129934.
Jiuyu Liu 1,  Pradeep B Lukka 2,  Victoria A Ektnitphong 3,  Keyur R Parmar 2,  Santosh Wagh 2,  Yan Lu 4,  Robin B Lee 1,  Dimitri Scherbakov 5,  Han Wang 6,  Matthew D Zimmerman 6,  Bernd Meibohm 2,  Gregory T Robertson 3,  Vêronique Dartois 6,  Erik C Böttger 5,  Anne J Lenaerts 3,  Richard E Lee 7
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, United States.
  • 2 Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
  • 3 Mycobacteria Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United States.
  • 4 Therapeutics Prod & Quality, St. Jude Children's Research Hospital, Memphis, TN, United States.
  • 5 Institut für Medizinische Mikrobiologie, Universität Zürich, Rämistrasse 71, Gloriastrasse 30/32, CH-8006 Zürich, Switzerland.
  • 6 The Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ 07103, United States.
  • 7 Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, United States. Electronic address: richard.lee@stjude.org.
PMID: 39214506 DOI: 10.1016/j.bmcl.2024.129934
Abstract

Spectinamides are a novel class of narrow-spectrum antitubercular agents with the potential to treat drug-resistant tuberculosis infections. Spectinamide 1810 has shown a good safety record following subcutaneous injection in mice or infusion in rats but exhibits transient acute toxicity following bolus administration in either species. To improve the therapeutic index of 1810, an injectable prodrug strategy was explored. The injectable phosphate prodrug 3408 has a superior maximum tolerated dose compared to 1810 or Gentamicin. Following intravenous administration in rodents, prodrug 3408 was quickly converted to 1810. The resulting 1810 exposure and pharmacokinetic profile after 3408 administration was identical to equivalent molar amounts of 1810 given directly by intravenous administration. 3408 and the parent 1810 exhibited similar overall efficacy in a BALB/c acute tuberculosis efficacy model. Delivery of 1810 in phosphate prodrug form, therefore, holds the potential to improve further the therapeutic index of an already promising tuberculosis Antibiotic.

Keywords

Phosphate Prodrug; Spectinamide; Tuberculosis.

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