title: Amino acid modified xanthone derivatives: novel, highly promising membrane-active antimicrobials for multidrug-resistant Gram-positive bacterial infections.
abstract: Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time-kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.
authors.affiliation: Singapore Eye Research Institute , 11 Third Hospital Avenue, 168751, Singapore.
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Koh
authors.forename: Shuimu
authors.initials: S
authors.lastname: Lin
authors.forename: Thet Tun
authors.initials: TT
authors.lastname: Aung
authors.forename: Fanghui
authors.initials: F
authors.lastname: Lim
authors.forename: Hanxun
authors.initials: H
authors.lastname: Zou
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.forename: Huifen
authors.initials: H
authors.lastname: Lin
authors.forename: Li Mei
authors.initials: LM
authors.lastname: Pang
authors.forename: Wee Luan
authors.initials: WL
authors.lastname: Koh
authors.forename: Shuhaida Mohamed
authors.initials: SM
authors.lastname: Salleh
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Qiu
authors.forename: Konstantin
authors.initials: K
authors.lastname: Pervushin
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.forename: Donald T H
authors.initials: DT
authors.lastname: Tan
authors.forename: Derong
authors.initials: D
authors.lastname: Cao
authors.forename: Shouping
authors.initials: S
authors.lastname: Liu
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D024901:Drug Resistance, Multiple, Bacterial; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D013329:Structure-Activity Relationship; D053835:Unilamellar Liposomes; D044004:Xanthones / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D053835:Unilamellar Liposomes; D044004:Xanthones