Scott Smith

Publications (2)12.73 Total impact

• Article: Isolation, structure and biological activity of phomafungin, a cyclic lipodepsipeptide from a widespread tropical Phoma sp.

  Kithsiri Herath, Guy Harris, Hiranthi Jayasuriya, Deborah Zink, Scott Smith, Francisca Vicente, Gerald Bills, Javier Collado, Antonio González, Bo Jiang, Jennifer Nielsen Kahn, Stefan Galuska, Robert Giacobbe, George Abruzzo, Emily Hickey, Paul Liberator, Deming Xu, Terry Roemer, Sheo B Singh
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  ABSTRACT: We isolated a cyclic lipodepsipeptide, phomafungin, from a Phoma sp. The distinct antifungal activity of phomafungin in the crude extract was initially discovered by mechanistic profiling in the Candida albicans fitness test. The purified compound contains a 28 member ring consisting of eight amino acids and a beta-hydroxy-gamma-methyl-hexadecanoic acid, and displays a broad spectrum of antifungal activity against Candida spp., Aspergillus fumigatus and Trichophyton mentagrophytes with MIC of 2-8 microg/ml, and toxicity to mice at 25 mg/kg. The linear peptide derived from opening of the lactone ring was devoid of antifungal activity as well as toxicity. Phomafungin has been identified in a number of Phoma spp. collected from Africa and the Indian and Pacific Ocean islands.
  Bioorganic & medicinal chemistry 01/2009; 17(3):1361-9. · 2.82 Impact Factor
• Article: Isolation, structure, and antibacterial activity of philipimycin, a thiazolyl peptide discovered from Actinoplanes philippinensis MA7347.

  Chaowei Zhang, James Occi, Prakash Masurekar, John F Barrett, Deborah L Zink, Scott Smith, Russell Onishi, Sookhee Ha, Oscar Salazar, Olga Genilloud, Angela Basilio, Francisca Vicente, Charles Gill, Emily J Hickey, Karen Dorso, Mary Motyl, Sheo B Singh
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  ABSTRACT: Bacterial resistance to antibiotics, particularly to multiple drug resistant antibiotics, is becoming cause for significant concern. The only really viable course of action is to discover new antibiotics with novel mode of actions. Thiazolyl peptides are a class of natural products that are architecturally complex potent antibiotics but generally suffer from poor solubility and pharmaceutical properties. To discover new thiazolyl peptides potentially with better desired properties, we designed a highly specific assay with a pair of thiazomycin sensitive and resistant strains of Staphylococcus aureus, which led to the discovery of philipimycin, a new thiazolyl peptide glycoside. It was isolated along with an acid-catalyzed degradation product by bioassay-guided fractionation. Structure of both compounds was elucidated by extensive application of 2D NMR, 1D TOCSY, and HRESIFT-MS/MS. Both compounds showed strong antibacterial activities against gram-positive bacteria including MRSA and exhibited MIC values ranging from 0.015 to 1 microg/mL. Philipimycin was significantly more potent than the degradation product. Both compounds showed selective inhibition of protein synthesis, indicating that they targeted the ribosome. Philipimycin was effective in vivo in a mouse model of S. aureus infection exhibiting an ED50 value of 8.4 mg/kg. The docking studies of philipimycin suggested that a part of the molecule interacts with the ribosome and another part with Pro23, Pro22, and Pro26 of L11 protein, which helped in explaining the differential of activities between the sensitive and resistant strains. The design and execution of the bioassay, the isolation, structure, in vitro and in vivo antibacterial activity, and docking studies of philipimycin and its degradation product are described.
  Journal of the American Chemical Society 10/2008; 130(36):12102-10. · 9.91 Impact Factor