title: A potent and selective antimicrobial poly(amidoamine) dendrimer conjugate with LED209 targeting QseC receptor to inhibit the virulence genes of gram negative bacteria.
abstract: The pandemic of multidrug-resistant Gram negative bacteria (GNB) is a worldwide healthcare concern, and very few antibiotics are being explored to match the clinical challenge. Recently, amino-terminated poly(amidoamine) (PAMAM) dendrimers have shown potential to function as broad antimicrobial agents. However, PAMAM displays a generation dependent cytotoxicity to mammalian cells and low selectivity on bacterial cells, which limits PAMAM to be developed as an antibacterial agent for systemic administration. We conjugated G3 PAMAM with LED209, a specific inhibitor of quorum sensor QseC of GNB, to generate a multifunctional agent PAMAM-LED209. Intriguingly, PAMAM-LED209 showed higher selectivity on GNB and lower cytotoxicity to mammalian cells, yet remained strong antibacterial activity. PAMAM-LED209 also inhibited virulence gene expression of GNB, and did not induce antibiotic-resistance. The present work firstly demonstrated that PAMAM-LED209 conjugate had a highly selective anti-GNB activity and low cytotoxicity, which offered a feasible strategy for combating multidrug-resistant GNB infections.
  
  
  BACKGROUND
  This research team demonstrated that a novel PAMAM-LED209 conjugate had highly selective activity against Gram-negative bacteria, coupled with low cytotoxicity, offering a potential strategy for combating multidrug-resistant infections.
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Xue
authors.affiliation: Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Xi'an, China.
authors.forename: Xing-Gang
authors.initials: XG
authors.lastname: Mao
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Ming-Kai
authors.initials: MK
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Meng
authors.affiliation: Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, China. Electronic address: xxluo3@fmmu.edu.cn.
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Luo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D007239:Infections / Q000188:drug therapy* / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage* / Q000737:chemistry; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D050091:Dendrimers; C531088:LED209; C104700:PAMAM Starburst; C434259:QscR protein, Pseudomonas aeruginosa; D012097:Repressor Proteins; D013449:Sulfonamides
keywords: Antimicrobial resistance; Gram negative bacteria; LED209; Poly(amidoamine) dendrimer; QseC