PUBLICATION
Antisense Oligonucleotide Activation via Enzymatic Antibiotic Resistance Mechanism
- Authors
- Darrah, K.E., Albright, S., Kumbhare, R., Tsang, M., Chen, J.K., Deiters, A.
- ID
- ZDB-PUB-230617-32
- Date
- 2023
- Source
- ACS Chemical Biology 18(10): 2176-2182 (Journal)
- Registered Authors
- Chen, James K., Tsang, Michael
- Keywords
- none
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/metabolism
- Anti-Bacterial Agents/pharmacology
- Bacteria/metabolism
- Cephalosporins/metabolism
- Drug Resistance, Microbial
- Gene Expression
- Mammals/genetics
- Mammals/metabolism
- Microbial Sensitivity Tests
- Oligonucleotides, Antisense*/pharmacology
- Zebrafish*/genetics
- beta-Lactamase Inhibitors
- beta-Lactamases/metabolism
- PubMed
- 37326511 Full text @ ACS Chem. Biol.
Citation
Darrah, K.E., Albright, S., Kumbhare, R., Tsang, M., Chen, J.K., Deiters, A. (2023) Antisense Oligonucleotide Activation via Enzymatic Antibiotic Resistance Mechanism. ACS Chemical Biology. 18(10):2176-2182.
Abstract
The structure and mechanism of the bacterial enzyme β-lactamase have been well-studied due to its clinical role in antibiotic resistance. β-Lactamase is known to hydrolyze the β-lactam ring of the cephalosporin scaffold, allowing a spontaneous self-immolation to occur. Previously, cephalosporin-based sensors have been developed to evaluate β-lactamase expression in both mammalian cells and zebrafish embryos. Here, we present a circular caged morpholino oligonucleotide (cMO) activated by β-lactamase-mediated cleavage of a cephalosporin motif capable of silencing the expression of T-box transcription factor Ta (tbxta), also referred to as no tail a (ntla), eliciting a distinct, observable phenotype. We explore the use of β-lactamase to elicit a biological response in aquatic embryos for the first time and expand the utility of cephalosporin as a cleavable linker beyond targeting antibiotic-resistant bacteria. The addition of β-lactamase to the current suite of enzymatic triggers presents unique opportunities for robust, orthogonal control over endogenous gene expression in a spatially resolved manner.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping