title: 5-Episinuleptolide Decreases the Expression of the Extracellular Matrix in Early Biofilm Formation of Multi-Drug Resistant Acinetobacter baumannii.
abstract: Nosocomial infections and increasing multi-drug resistance caused by Acinetobacter baumannii have been recognized as emerging problems worldwide. Moreover, A. baumannii is able to colonize various abiotic materials and medical devices, making it difficult to eradicate and leading to ventilator-associated pneumonia, and bacteremia. Development of novel molecules that inhibit bacterial biofilm formation may be an alternative prophylactic option for the treatment of biofilm-associated A. baumannii infections. Marine environments, which are unlike their terrestrial counterparts, harbor an abundant biodiversity of marine organisms that produce novel bioactive natural products with pharmaceutical potential. In this study, we identified 5-episinuleptolide, which was isolated from Sinularia leptoclados, as an inhibitor of biofilm formation in ATCC 19606 and three multi-drug resistant A. baumannii strains. In addition, the anti-biofilm activities of 5-episinuleptolide were observed for Gram-negative bacteria but not for Gram-positive bacteria, indicating that the inhibition mechanism of 5-episinuleptolide is effective against only Gram-negative bacteria. The mechanism of biofilm inhibition was demonstrated to correlate to decreased gene expression from the pgaABCD locus, which encodes the extracellular polysaccharide poly-β-(1,6)-N-acetylglucosamine (PNAG). Scanning electron microscopy (SEM) indicated that extracellular matrix of the biofilm was dramatically decreased by treatment with 5-episinuleptolide. Our study showed potentially synergistic activity of combination therapy with 5-episinuleptolide and levofloxacin against biofilm formation and biofilm cells. These data indicate that inhibition of biofilm formation via 5-episinuleptolide may represent another prophylactic option for solving the persistent problem of biofilm-associated A. baumannii infections.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan. tsengsp@kmu.edu.tw.|Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan. tsengsp@kmu.edu.tw.
authors.forename: Sung-Pin
authors.initials: SP
authors.lastname: Tseng
authors.affiliation: Department of Microbiology and Immunology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. wchung@kmu.edu.tw.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan. huangcy@mail.nsysu.edu.tw.
authors.forename: Chiung-Yao
authors.initials: CY
authors.lastname: Huang
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan. cookiecandy760428@hotmail.com.
authors.forename: Yin-Shiou
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, College of Health Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan. min116min@yahoo.com.tw.
authors.forename: Min-Yu
authors.initials: MY
authors.lastname: Chan
authors.affiliation: Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. d830166@cc.kmu.edu.tw.|College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. d830166@cc.kmu.edu.tw.|Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. d830166@cc.kmu.edu.tw.
authors.forename: Po-Liang
authors.initials: PL
authors.lastname: Lu
authors.affiliation: Department of Culinary Art, I-Shou University, Kaohsiung 840, Taiwan. chang1025@msn.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 804, Taiwan. sheu@mail.nsysu.edu.tw.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan. sheu@mail.nsysu.edu.tw.|Asia Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 804, Taiwan. sheu@mail.nsysu.edu.tw.|Frontier Center for Ocean Science and Technology, National Sun Yat-sen University, Kaohsiung 804, Taiwan. sheu@mail.nsysu.edu.tw.
authors.forename: Jyh-Horng
authors.initials: JH
authors.lastname: Sheu
mesh_terms: D000151:Acinetobacter Infections / Q000382:microbiology / Q000517:prevention & control*; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D000818:Animals; D037421:Anthozoa / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology; D003428:Cross Infection / Q000382:microbiology / Q000517:prevention & control*; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004866:Equipment Contamination; D005109:Extracellular Matrix / Q000187:drug effects / Q000648:ultrastructure; D005798:Genes, Bacterial / Q000187:drug effects; D006801:Humans; D064704:Levofloxacin / Q000494:pharmacology; D008855:Microscopy, Electron, Scanning; D047071:beta-Glucans / Q000378:metabolism
chemical_list: C520059:5-episinuleptolide; D000900:Anti-Bacterial Agents; D001688:Biological Products; D004224:Diterpenes; D047071:beta-Glucans; C505465:poly-N-acetyl-1-6-glucosamine; D064704:Levofloxacin
keywords: 5-Episinuleptolide; biofilm; multi-drug resistant A. baumannii