2. Academic Validation
  3. Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead

Forgotten Natural Products: Semisynthetic Development of Blasticidin S As an Antibiotic Lead

  • ACS Med Chem Lett. 2024 Feb 23;15(3):362-368. doi: 10.1021/acsmedchemlett.3c00527.
Cole Gannett 1 2,  Kateland Tiller 2 3,  Anthony J Briganti 4,  Anne M Brown 2 4 5 6,  James Weger-Lucarelli 2 3,  Andrew N Lowell 1 2 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
  • 2 Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
  • 3 Department of Biomedical Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, Virginia 24061, United States.
  • 4 Department of Biochemistry, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 5 Research and Informatics, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 6 Interdisciplinary Program in Genetics, Bioinformatics, and Computational Biology, Virginia Tech, Blacksburg, Virginia 24061, United States.
  • 7 Faculty of Health Sciences, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.
PMID: 38505852 DOI: 10.1021/acsmedchemlett.3c00527
Abstract

Forgotten natural products offer value as antimicrobial scaffolds, providing diverse mechanisms of action that complement existing Antibiotic classes. This study focuses on the derivatization of the cytotoxin blasticidin S, seeking to leverage its unique ribosome inhibition mechanism. Despite its complex zwitterionic properties, a selective protection and amidation strategy enabled the creation of a library of blasticidin S derivatives including the natural product P10. The amides exhibited significantly increased activity against Gram-positive bacteria and enhanced specificity for pathogenic bacteria over human cells. Molecular docking and computational property analysis suggested variable binding poses and indicated a potential correlation between cLogP values and activity. This work demonstrates how densely functionalized forgotten antimicrobials can be straightforwardly modified, enabling the further development of blasticidin S derivatives as lead compounds for a novel class of Antibiotics.

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