- Inhibition of Isoleucyl-tRNA Synthetase by the Hybrid Antibiotic Thiomarinol
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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.
- Johnson, Rachel A.,Chan, Andrew N.,Ward, Ryan D.,McGlade, Caylie A.,Hatfield, Breanne M.,Peters, Jason M.,Li, Bo
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- Reducing Holomycin Thiosulfonate to its Disulfide with Thiols
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The dithiolopyrrolone (DTP) natural products contain a unique ene-disulfide that is essential for their antimicrobial and anticancer activities. The ene-disulfide in some DTPs is oxidized to a cyclic thiosulfonate, but it is unknown how the DTP thiosulfonates react with biomolecules. We studied the reactivity of the thiosulfonate derivative of the DTP holomycin, oxo-holomycin, and discovered a unique redox reaction: Oxo-holomycin is reduced to its parent disulfide, while oxidizing small molecule and protein thiols to disulfides. Our work reveals that the DTP core is a privileged scaffold that undergoes unusual redox chemistry. The redox chemistry of the DTP natural products may contribute to their mechanism of action.
- Chan, Andrew N.,Massolo, Elisabetta,Li, Bo,Wever, Walter J.,Allen, Scott E.
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- Thiomarinol, a new hybrid antimicrobial antibiotic produced by a marine bacterium. Fermentation, isolation, structure, and antimicrobial activity
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Thiomarinol, an antimicrobial antibiotic, was isolated from the culture broth of a marine bacterium, Alteromonas rava sp. nov. SANK 73390. Its structure was deduced as a hybrid composed of a pseudomonic acid analogue and holothin by NMR spectral analysis and chemical degradation. Antimicrobial activity against Gram-positive and Gram-negative bacteria of thiomarinol was stronger than both of pseudomonic acids and pyrrothine antibiotics.
- Shiozawa,Kagasaki,Kinoshita,Haruyama,Domon,Utsui,Kodama,Takahashi
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- Expedient total synthesis of pyrrothine natural products and analogs
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This paper describes an expedient and straightforward total synthesis of the two pyrrothine natural products holomycin 1a (7 steps, 11% overall) and xenorhabdin I 1c (7 steps, 11% overall) and analogs thereof via a common late-stage intermediate. The path
- Hjelmgaard, Thomas,Givskov, Michael,Nielsen, John
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p. 344 - 348
(2008/03/27)
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