Zero Hunger (SDG 2), Good Health & Well-being (SDG 3)
Triplex-Forming Oligonucleotides as an Anti-Gene Antibiotic strategy
Isobella S.J. Stone* and Tara L. Pukala Department of Chemistry, University of Adelaide, Australia
Resistance of pathogens to once effective therapeutics is a pressing global health concern, with an estimated five million deaths linked to bacterial anti-microbial resistance annually. 1 This growing health- care crisis is exacerbated by the substantial slowdown in the development of new clinically relevant classes of antibiotics in past decades. An innovative strategy to combat bacterial infections is emerging in anti-gene technology, where an oligonucleotide is designed to bind key DNA sequences, preventing transcription and thus controlling expression of key genes for bacterial survival. 2 In our research, we investigate the potential of triple-helix DNA formation as an anti-gene approach. Triplex-forming oligonucleotides (TFOs) have been found to bind in the major groove of Watson-Crick duplex DNA, but the incidence is limited to poly-purine sequences and suffers from low stability.3 In order to exploit this phenomenon for anti-gene therapeutics we are working to improve the fundamental understanding and characterisation of DNA triplexes, as well as rationally design and synthesise artificial oligonucleotides with improved scope and stability. We will discuss the variety of techniques we have explored to synthetically modify nucleobases and oligonucleotides to investigate and enhance third strand binding, targeting key sequences for survival in the bacteria E. coli as a proof of concept. References 1. Murray, C. J. L.; et al., Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 2022, 399 (10325), 629-655. 2. Sully, E. K.; Geller, B. L., Antisense antimicrobial therapeutics. Current opinion in microbiology 2016, 33, 47-55. 3. Fox, K. R.; Brown, T.; Rusling, D. A., Chapter 1 DNA Recognition by Parallel Triplex Formation. In DNA-targeting Molecules as Therapeutic Agents, The Royal Society of Chemistry: 2018; pp 1-32.
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© The Author(s), 2023
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