4.8 Article

Inhibition of Isoleucyl-tRNA Synthetase by the Hybrid Antibiotic Thiomarinol

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 31, Pages 12003-12013

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c02622

Keywords

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Funding

  1. National Institutes of Health [DP2HD094657]
  2. Packard Fellowship for Science and Engineering
  3. NIH National Institute of Allergy and Infectious Diseases [K22AI137122]
  4. UNC Chapel Hill
  5. Predoctoral Training Program in Genetics [5T32GM007133-46]
  6. Clare Boothe Luce Fellowship for Women in Science
  7. Molecular and Cellular Biophysics Training Grant [T32GM008570]

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Hybrid antibiotics like thiomarinol A show promise in combating antibiotic resistance, with a dual mode of action targeting IleRS and potentially involving metal chelation. Thiomarinol A remains effective against high-level mupirocin-resistant MRSA and shows less resistance development compared to mupirocin, emphasizing the importance of hybridity between DTP and mupirocin for potent activity.
Hybrid antibiotics are an emerging antimicrobial strategy to overcome antibiotic resistance. The natural product thiomarinol A is a hybrid of two antibiotics: holothin, a dithiolopyrrolone (DTP), and marinolic acid, a close analogue of the drug mupirocin that is used to treat methicillin-resistant Staphylococcus aureus (MRSA). DTPs disrupt metal homeostasis by chelating metal ions in cells, whereas mupirocin targets the essential enzyme isoleucyl-tRNA synthetase (IleRS). Thiomarinol A is over 100-fold more potent than mupirocin against mupirocin-sensitive MRSA; however, its mode of action has been unknown. We show that thiomarinol A targets IleRS. A knockdown of the IleRS-encoding gene, ileS, exhibited sensitivity to a synthetic analogue of thiomarinol A in a chemical genomics screen. Thiomarinol A inhibits MRSA IleRS with a picomolar Ki and binds to IleRS with low femtomolar affinity, 1600 times more tightly than mupirocin. We find that thiomarinol A remains effective against high-level mupirocin-resistant MRSA and provide evidence to support a dual mode of action for thiomarinol A that may include both IleRS inhibition and metal chelation. We demonstrate that MRSA develops resistance to thiomarinol A to a substantially lesser degree than mupirocin and the potent activity of thiomarinol A requires hybridity between DTP and mupirocin. Our findings identify a mode of action of a natural hybrid antibiotic and demonstrate the potential of hybrid antibiotics to combat antibiotic resistance.

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