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Chrysomycin A inhibits the topoisomerase I of Mycobacterium tuberculosis

The Journal of Antibiotics volume 75, pages 226–235 (2022)Cite this article

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Abstract

Novel anti-tuberculosis drugs are essential to manage drug-resistant tuberculosis, caused by Mycobacterium tuberculosis. We recently reported the antimycobacterial activity of chrysomycin A in vitro and in infected macrophages. In this study, we report that it inhibits the growth of drug-resistant clinical strains of M. tuberculosis and acts in synergy with anti-TB drugs such as ethambutol, ciprofloxacin, and novobiocin. In pursuit of its mechanism of action, it was found that chrysomycin A is bactericidal and exerts this activity by interacting with DNA at specific sequences and by inhibiting the topoisomerase I activity of M. tuberculosis. It also exhibits weak inhibition of the DNA gyrase enzyme of the pathogen.

Highlights

  • Chrysomycin A inhibits the growth of susceptible, multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical strains of Mycobacterium tuberculosis.

  • It intercalates DNA at preferred sequences rather than randomly.

  • It inhibits mycobacterial topoisomerase I activity in vitro.

  • It also exhibits modest inhibition of mycobacterial DNA gyrase activity.

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Acknowledgements

BM thanks the Council of Scientific Industrial Research, Govt. of India for a research fellowship and RAK thanks the Department of Biotechnology, Govt. of India for funding. We are grateful to Ms. Arthi R and Dr. Kana M Sureshan, School of Chemistry, Indian Institutes of Science Education and Research, Thiruvananthapuram, for their help in fluorescence spectrometry and circular dichroism studies.

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Authors and Affiliations

  1. Mycobacterium Research Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India

    Balaji Muralikrishnan, Lekshmi K. Edison, G. R. Jijimole, Ranjit Ramachandran, Aravind Madhavan & Ramakrishnan Ajay Kumar

  2. Department of Bacteriology, National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India

    Azger Dusthackeer

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  1. Balaji Muralikrishnan
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Correspondence to Ramakrishnan Ajay Kumar.

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Muralikrishnan, B., Edison, L.K., Dusthackeer, A. et al. Chrysomycin A inhibits the topoisomerase I of Mycobacterium tuberculosis. J Antibiot 75, 226–235 (2022). https://doi.org/10.1038/s41429-022-00503-z

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