title: Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa.
abstract: Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the beta-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.
authors.affiliation: Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors.forename: Nityakalyani
authors.initials: N
authors.lastname: Srinivas
authors.forename: Peter
authors.initials: P
authors.lastname: Jetter
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Ueberbacher
authors.forename: Martina
authors.initials: M
authors.lastname: Werneburg
authors.forename: Katja
authors.initials: K
authors.lastname: Zerbe
authors.forename: Jessica
authors.initials: J
authors.lastname: Steinmann
authors.forename: Benjamin
authors.initials: B
authors.lastname: Van der Meijden
authors.forename: Francesca
authors.initials: F
authors.lastname: Bernardini
authors.forename: Alexander
authors.initials: A
authors.lastname: Lederer
authors.forename: Ricardo L A
authors.initials: RL
authors.lastname: Dias
authors.forename: Pauline E
authors.initials: PE
authors.lastname: Misson
authors.forename: Heiko
authors.initials: H
authors.lastname: Henze
authors.forename: Jürg
authors.initials: J
authors.lastname: Zumbrunn
authors.forename: Frank O
authors.initials: FO
authors.lastname: Gombert
authors.forename: Daniel
authors.initials: D
authors.lastname: Obrecht
authors.forename: Peter
authors.initials: P
authors.lastname: Hunziker
authors.forename: Stefan
authors.initials: S
authors.lastname: Schauer
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.forename: Andres
authors.initials: A
authors.lastname: Käch
authors.forename: Leo
authors.initials: L
authors.lastname: Eberl
authors.forename: Kathrin
authors.initials: K
authors.lastname: Riedel
authors.forename: Steven J
authors.initials: SJ
authors.lastname: DeMarco
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000235:genetics; D005798:Genes, Bacterial; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D009154:Mutation; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001425:Bacterial Outer Membrane Proteins; D008070:Lipopolysaccharides; D019151:Peptide Library; D010455:Peptides; C094880:protegrin-1