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Biosynthetically Guided Structure-Activity Relationship Studies of Merochlorin A, an Antibiotic Marine Natural Product.
López-Pérez, Borja; Pepper, Henry P; Ma, Rong; Fawcett, Benjamin J; Pehere, Ashok D; Wei, Qi; Ji, Zengchun; Polyak, Steven W; Dai, Huanqin; Song, Fuhang; Abell, Andrew D; Zhang, Lixin; George, Jonathan H.
Affiliation
  • López-Pérez B; Department of Chemistry, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • Pepper HP; Department of Chemistry, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • Ma R; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
  • Fawcett BJ; Department of Chemistry, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • Pehere AD; Department of Chemistry, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • Wei Q; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
  • Ji Z; College of Life Science, Hebei University, Baoding, 071002, P.R. China.
  • Polyak SW; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
  • Dai H; School of Biological Engineering, Tianjin University of Science and Technology, Tianjin, 300457, P.R. China.
  • Song F; Department of Molecular and Cellular Biology, University of Adelaide, Adelaide, South Australia, 5005, Australia.
  • Abell AD; Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
  • Zhang L; Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
  • George JH; Department of Chemistry, University of Adelaide, Adelaide, South Australia, 5005, Australia.
ChemMedChem ; 12(23): 1969-1976, 2017 12 07.
Article in En | MEDLINE | ID: mdl-29168322
ABSTRACT
The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorin A that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12 c {(±)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guérin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Biological Products / Erythrocytes / Sesterterpenes / Gram-Positive Bacteria / Anti-Bacterial Agents Limits: Animals Language: En Journal: ChemMedChem Journal subject: FARMACOLOGIA / QUIMICA Year: 2017 Document type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Biological Products / Erythrocytes / Sesterterpenes / Gram-Positive Bacteria / Anti-Bacterial Agents Limits: Animals Language: En Journal: ChemMedChem Journal subject: FARMACOLOGIA / QUIMICA Year: 2017 Document type: Article Affiliation country: Australia