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Symmetrically Substituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistance with Enhanced Membrane Selectivity.
Lin, Shuimu; Koh, Jun-Jie; Aung, Thet Tun; Lim, Fanghui; Li, Jianguo; Zou, Hanxun; Wang, Lin; Lakshminarayanan, Rajamani; Verma, Chandra; Wang, Yingjun; Tan, Donald T H; Cao, Derong; Beuerman, Roger W; Ren, Li; Liu, Shouping.
Afiliación
  • Lin S; School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.
  • Koh JJ; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Aung TT; National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou 510006, China.
  • Lim F; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Li J; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Zou H; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Wang L; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Lakshminarayanan R; Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 Matrix, 138671, Singapore.
  • Verma C; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Wang Y; School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.
  • Tan DT; National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou 510006, China.
  • Cao D; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Beuerman RW; SRP Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School , 169857, Singapore.
  • Ren L; Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
  • Liu S; Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 Matrix, 138671, Singapore.
J Med Chem ; 60(4): 1362-1378, 2017 02 23.
Article en En | MEDLINE | ID: mdl-28122182
This is the first report of the design of a new series of symmetric xanthone derivatives that mimic antimicrobial peptides using a total synthesis approach. This novel design is advantageous because of its low cost, synthetic simplicity and versatility, and easy tuning of amphiphilicity by controlling the incorporated cationic and hydrophobic moieties. Two water-soluble optimized compounds, 6 and 18, showed potent activities against Gram-positive bacteria, including MRSA and VRE (MICs = 0.78-6.25 µg/mL) with a rapid bactericidal effect, low toxicity, and no emergence of drug resistance. Both compounds demonstrated enhanced membrane selectivity that was higher than those of most membrane-active antimicrobials in clinical trials or previous reports. The compounds appear to kill bacteria by disrupting their membranes. Significantly, 6 was effective in vivo using a mouse model of corneal infection. These results provide compelling evidence that these compounds have therapeutic potential as novel antimicrobials for multidrug-resistant Gram-positive infections.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Métodos Terapéuticos y Terapias MTCI: Plantas_medicinales Asunto principal: Infecciones Estafilocócicas / Xantonas / Staphylococcus aureus Resistente a Meticilina / Antibacterianos Idioma: En Revista: J Med Chem Año: 2017 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Métodos Terapéuticos y Terapias MTCI: Plantas_medicinales Asunto principal: Infecciones Estafilocócicas / Xantonas / Staphylococcus aureus Resistente a Meticilina / Antibacterianos Idioma: En Revista: J Med Chem Año: 2017 Tipo del documento: Article País de afiliación: China