Development of novel antibacterial peptides that kill resistant isolates.
The rapid emergence of bacterial strains that are resistant to current antibiotics requires the development of novel types of antimicrobial compounds. Proline-rich cationic antibacterial peptides such as pyrrhocoricin kill responsive bacteria by binding to the 70 kDa heat shock protein DnaK and inhibiting protein folding. We designed and synthesized multiply protected dimeric analogs of pyrrhocoricin and optimized the in vitro antibacterial efficacy assays for peptide antibiotics. Pyrrhocoricin and the designed dimers killed beta-lactam, tetracycline- or aminoglycoside-resistant strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the submicromolar or low micromolar concentration range. One of the peptides also killed Pseudomonas aeruginosa. The designed dimers showed improved stability in mammalian sera compared to the native analog. In a murine H. influenzae lung infection model, a single dose of a dimeric pyrrhocoricin analog reduced the bacteria in the bronchoalveolar lavage when delivered intranasally. The solid-phase synthesis was optimized for large-scale laboratory preparations.
Cudic
Mare
M
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Condie
Barry A
BA
Weiner
Daniel J
DJ
Lysenko
Elena S
ES
Xiang
Zhi Q
ZQ
Insug
O
O
Bulet
Philippe
P
Otvos
Laszlo
L
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D006193:Haemophilus influenzae / Q000187:drug effects; D019476:Insect Proteins; D008745:Methylation; D010455:Peptides / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D019476:Insect Proteins; D010455:Peptides; C087710:pyrrhocoricin protein, Pyrrhocoris apterus