title: Amphiphilic xanthones as a potent chemical entity of anti-mycobacterial agents with membrane-targeting properties.
abstract: Tuberculosis (TB) remains a deadly disease and infects one-third of the world's population. Given the low success rates encountered in clinical development, there is an urgent need to identify structurally novel antimicrobials for tuberculosis. The present report details the anti-mycobacterial activities, structure-activity relationships (SARs) and mechanism of action of amphiphilic xanthone derivatives. The xanthones exhibited potent MIC, rapid time-kill and no cross-resistance with the current anti-TB drugs. Evidence is presented that these compounds disrupted the inner membrane and led to ATP depletion. Amphiphilic xanthone derivatives exhibited superior metabolic stability, low cytotoxicity and low activity against the common cytochrome P450. Compound 5 was selected for an in vivo pharmacokinetic study. Its bioavailability at an oral dose of 2 mg/kg was 15%. The xanthones thuse provide valuable insight for the development of a new class of membrane targeting antimycobacterial agents that may assist in overcoming the limitations of the current TB medications.
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 119074, Singapore.
authors: Jun-Jie
authors: JJ
authors: Koh
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors: Hanxun
authors: H
authors: Zou
authors: Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545, Singapore.
authors: Devika
authors: D
authors: Mukherjee
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors: Shuimu
authors: S
authors: Lin
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors: Fanghui
authors: F
authors: Lim
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors: Javey Khiapeng
authors: JK
authors: Tan
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore.
authors: Dhi-Zen
authors: DZ
authors: Tan
authors: Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.
authors: Bridget L
authors: BL
authors: Stocker
authors: Victoria University of Wellington, School of Chemical and Physical Science, PO Box 600, Wellington, New Zealand.
authors: Mattie S M
authors: MSM
authors: Timmer
authors: Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand; Victoria University of Wellington, School of Chemical and Physical Science, PO Box 600, Wellington, New Zealand.
authors: Hilary M
authors: HM
authors: Corkran
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Duke-NUS Medical School, SRP Neuroscience and Behavioural Disorders, 169857, Singapore.
authors: Rajamani
authors: R
authors: Lakshminarayanan
authors: Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore.
authors: Donald T H
authors: DTH
authors: Tan
authors: School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China.
authors: Derong
authors: D
authors: Cao
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Duke-NUS Medical School, SRP Neuroscience and Behavioural Disorders, 169857, Singapore. Electronic address: rwbeuerman@gmail.com.
authors: Roger W
authors: RW
authors: Beuerman
authors: Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 117545, Singapore. Electronic address: thomas_dick@nuhs.edu.sg.
authors: Thomas
authors: T
authors: Dick
authors: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 6, 169856, Singapore; Duke-NUS Medical School, SRP Neuroscience and Behavioural Disorders, 169857, Singapore. Electronic address: liushouping@gmail.com.
authors: Shouping
authors: S
authors: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D051381:Rats; D044004:Xanthones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000995:Antitubercular Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D044004:Xanthones; D000255:Adenosine Triphosphate
keywords: Membrane targeting; Mycobacteria; Tuberculosis; Xanthone