title: Symmetrically Substituted Xanthone Amphiphiles Combat Gram-Positive Bacterial Resistance with Enhanced Membrane Selectivity.
abstract: 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.
authors.affiliation: School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.|Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou 510006, China.
authors.forename: Shuimu
authors.initials: S
authors.lastname: Lin
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Koh
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Thet Tun
authors.initials: TT
authors.lastname: Aung
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Fanghui
authors.initials: F
authors.lastname: Lim
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 Matrix, 138671, Singapore.
authors.forename: Jianguo
authors.identifier: 0000-0002-5544-6451
authors.initials: J
authors.lastname: Li
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors.forename: Hanxun
authors.initials: H
authors.lastname: Zou
authors.affiliation: School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.|National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou 510006, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|SRP Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School , 169857, Singapore.
authors.forename: Rajamani
authors.identifier: 0000-0001-8214-5315
authors.initials: R
authors.lastname: Lakshminarayanan
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|Bioinformatics Institute (A*STAR) , 30 Biopolis Street, 07-01 Matrix, 138671, Singapore.|School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637551, Singapore.|Department of Biological Sciences, National University of Singapore , 14 Science Drive 4, 117543, Singapore.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.|National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou 510006, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|Singapore National Eye Center , 11 Third Hospital Avenue, 168751, Singapore.
authors.forename: Donald T H
authors.initials: DT
authors.lastname: Tan
authors.affiliation: School of Chemistry and Chemical Engineering, South China University of Technology , Guangzhou 510641, China.
authors.forename: Derong
authors.initials: D
authors.lastname: Cao
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|SRP Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School , 169857, Singapore.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
authors.affiliation: School of Materials Science and Engineering, South China University of Technology , Guangzhou 510641, China.|National Engineering Research Center for Tissue Restoration and Reconstruction , Guangzhou 510006, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ren
authors.affiliation: Singapore Eye Research Institute, The Academia , 20 College Road, Discovery Tower Level 6, 169856, Singapore.|SRP Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School , 169857, Singapore.
authors.forename: Shouping
authors.identifier: 0000-0003-2415-076X
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D003315:Cornea / Q000382:microbiology; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013501:Surface-Active Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D044004:Xanthones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D013501:Surface-Active Agents; D044004:Xanthones