Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa.
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.
Srinivas
Nityakalyani
N
Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Jetter
Peter
P
Ueberbacher
Bernhard J
BJ
Werneburg
Martina
M
Zerbe
Katja
K
Steinmann
Jessica
J
Van der Meijden
Benjamin
B
Bernardini
Francesca
F
Lederer
Alexander
A
Dias
Ricardo L A
RL
Misson
Pauline E
PE
Henze
Heiko
H
Zumbrunn
Jürg
J
Gombert
Frank O
FO
Obrecht
Daniel
D
Hunziker
Peter
P
Schauer
Stefan
S
Ziegler
Urs
U
Käch
Andres
A
Eberl
Leo
L
Riedel
Kathrin
K
DeMarco
Steven J
SJ
Robinson
John A
JA
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
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001425:Bacterial Outer Membrane Proteins; D008070:Lipopolysaccharides; D019151:Peptide Library; D010455:Peptides; C094880:protegrin-1