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Albany 2019: 20th Conversation - Abstracts

Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

DNA topoisomerases as targets for antibacterial chemotherapy

DNA topoisomerases are enzymes that catalyze changes in DNA topology (1). There are two types, I and II, differentiated by whether they catalyze reactions via single- or double-stranded breaks in DNA. They are essential in all cells, having key roles in DNA replication, transcription and recombination. All topoisomerases are able to relax supercoiled DNA, but DNA gyrase, essential in all bacteria, can also introduce negative supercoils in a reaction coupled to ATP hydrolysis (2). Due to their essential nature and the fact that they stabilize single- or double-stranded breaks in DNA, topoisomerases have become key drug targets both for antibacterial and anti-cancer chemotherapy (2-4).

Building on structural and mechanistic data, we have focused on antibiotics targeted to bacterial gyrase. Fluoroquinolone drugs (e.g. ciprofloxacin) have been highly-successful. Their mechanism involves stabilization of a protein-linked transient double-strand break in DNA, which can be lethal. However, resistance to fluoroquinolones is significant and alternative compounds are needed. Although aminocoumarin natural products (e.g. novobiocin) are potential alternatives, these compounds have not achieved significant clinical success. Working with pharma companies we have investigated other compounds that stabilize the gyrase-DNA cleavage complex, e.g. IPYs (5,6) and thiophenes (7) (Figure). The potential of these and other compounds as future antibiotics will be discussed.

References

    1. Bates, A.D. and Maxwell, A. (2005) DNA Topology. Oxford University Press, Oxford

    2. Collin, F., Karkare, S. and Maxwell, A. (2011) Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol, 92, 479-497.

    3. Pommier, Y., Leo, E., Zhang, H. and Marchand, C. (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol, 17, 421-433.

    4. Maxwell, A., Bush, N.G., Germe, T. and McKie, S.J. (2018) In Fong, I. W., Shlaes, D. and Drlica, K. (eds.), Antimicrobial resistance and implications for the 21st century. Springer, Switzerland.

    5. Germe, T., Voros, J., Jeannot, F., Taillier, T., Stavenger, R.A., Bacque, E., Maxwell, A. and Bax, B.D. (2018) A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Res, 46, 4114-4128.

    6. Jeannot, F., Taillier, T., Despeyroux, P., Renard, S., Rey, A., Mourez, M., Poeverlein, C., Khichane, I., Perrin, M.A., Versluys, S. et al. (2018) Imidazopyrazinones (IPYs): Non-Quinolone Bacterial Topoisomerase Inhibitors Showing Partial Cross-Resistance with Quinolones. J Med Chem, 61, 3565-3581.

    7. Chan, P.F., Germe, T., Bax, B.D., Huang, J., Thalji, R.K., Bacque, E., Checchia, A., Chen, D., Cui, H., Ding, X. et al. (2017) Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proc Natl Acad Sci U S A, 114, E4492-E4500.

Anthony Maxwell

Department of Biological Chemistry
John Innes Centre
Norwich Research Park
Norwich NR4 7UH, UK

Ph: +44 1603 450771
Email: tony.maxwell@jic.ac.uk

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Figure – shows a cartoon of a truncated gyrase-DNA complex highlighting the sites of action of antibiotics