Chrysomycin A inhibits the topoisomerase I of Mycobacterium tuberculosis

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...

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Bibliographic Details
Published in:Journal of antibiotics 2022-04, Vol.75 (4), p.226-235
Main Authors: Muralikrishnan, Balaji, Edison, Lekshmi K., Dusthackeer, Azger, Jijimole, G. R., Ramachandran, Ranjit, Madhavan, Aravind, Kumar, Ramakrishnan Ajay
Format: Article
Language:English
Subjects:
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Bacteriology
Biomedical and Life Sciences
Bioorganic Chemistry
Ciprofloxacin
Deoxyribonucleic acid
DNA
DNA topoisomerase
Drug resistance
Drugs
Ethambutol
Gene sequencing
Intercalating agents
Life Sciences
Macrophages
Medicinal Chemistry
Microbiology
Multidrug resistance
Mycobacterium tuberculosis
Novobiocin
Nucleotide sequence
Organic Chemistry
Tuberculosis
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Summary: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.
ISSN:0021-8820
1881-1469
DOI:10.1038/s41429-022-00503-z