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Design, Synthesis, and Biological Evaluation of Light-Activated Antibiotics


Shchelik, Inga S; Tomio, Andrea; Gademann, Karl (2021). Design, Synthesis, and Biological Evaluation of Light-Activated Antibiotics. ACS Infectious Diseases, 7(3):681-692.

Abstract

The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different ‘caged’ antibiotic classes that can undergo remote activation with UV-light at λ=365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thus suppressing undesired off-site activity. The antimicrobial activity against Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 29213, S. aureus ATCC 43300 (MRSA), Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.

Abstract

The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different ‘caged’ antibiotic classes that can undergo remote activation with UV-light at λ=365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thus suppressing undesired off-site activity. The antimicrobial activity against Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 29213, S. aureus ATCC 43300 (MRSA), Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Health Sciences > Infectious Diseases
Uncontrolled Keywords:Infectious Diseases, antibacterial agents, photopharmacology, photocaging, vancomycin, cephalosporin.
Language:English
Date:12 March 2021
Deposited On:17 Jan 2022 16:22
Last Modified:27 Mar 2024 03:06
Publisher:American Chemical Society (ACS)
ISSN:2373-8227
OA Status:Green
Publisher DOI:https://doi.org/10.1021/acsinfecdis.1c00015
Project Information:
  • : FunderSNSF
  • : Grant ID200021_182043
  • : Project TitleMechanism-Based Design, Synthesis, Biological Evaluation, and Delivery of Next-Generation Antibiotics
  • : FunderBundesbeh?rden der Schweizerischen Eidgenossenschaft
  • : Grant ID
  • : Project Title
  • Content: Accepted Version
  • Language: English