title: An Amphipathic Undecapeptide with All d-Amino Acids Shows Promising Activity against Colistin-Resistant Strains of Acinetobacter baumannii and a Dual Mode of Action.
abstract: Multiple strains of Acinetobacter baumannii have developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-α-melittin hybrid BP100 (KKLFKKILKYL-NH2) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated the in vitro antibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDR A. baumannii strain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains of A. baumannii that acquired resistance to colistin due to mutations of the lpxC, lpxD, pmrA, and pmrB genes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 μM and a hemolytic 50% effective concentration (EC50) of >150 μM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 when pmrAB and lpxC mutants were challenged.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark alberto.oddo@sund.ku.dk lobner@bio.ku.dk prh@sund.ku.dk.
authors.forename: Alberto
authors.initials: A
authors.lastname: Oddo
authors.affiliation: Department of Biology, Center for Bacterial Stress Response and Persistence, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Thomsen
authors.affiliation: Department of Biology, Center for Bacterial Stress Response and Persistence, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kjelstrup
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ciara
authors.initials: C
authors.lastname: Gorey
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Franzyk
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Niels
authors.identifier: http://orcid.org/0000-0003-1966-8302
authors.initials: N
authors.lastname: Frimodt-Møller
authors.affiliation: Department of Biology, Center for Bacterial Stress Response and Persistence, University of Copenhagen, Copenhagen, Denmark alberto.oddo@sund.ku.dk lobner@bio.ku.dk prh@sund.ku.dk.
authors.forename: Anders
authors.initials: A
authors.lastname: Løbner-Olesen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark alberto.oddo@sund.ku.dk lobner@bio.ku.dk prh@sund.ku.dk.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hansen
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D003091:Colistin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects; D015870:Gene Expression; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D060327:Solid-Phase Synthesis Techniques; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009842:Oligopeptides; C409039:PmrB protein, bacteria; D014157:Transcription Factors; C540525:lysyl-lysyl-leucyl-phenylalanyl-lysyl-lysyl-isoleucyl-leucyl-lysyl-tyrosyl-leucinamide; C081902:pmrA protein, Bacteria; D000217:Acyltransferases; D000581:Amidohydrolases; D003091:Colistin