Designer antibacterial peptides kill fluoroquinolone-resistant clinical isolates.
A significant number of Escherichia coli and Klebsiella pneumoniae bacterial strains in urinary tract infections are resistant to fluoroquinolones. Peptide antibiotics are viable alternatives although these are usually either toxic or insufficiently active. By applying multiple alignment and sequence optimization steps, we designed multifunctional proline-rich antibacterial peptides that maintained their DnaK-binding ability in bacteria and low toxicity in eukaryotes, but entered bacterial cells much more avidly than earlier peptide derivatives. The resulting chimeric and statistical analogues exhibited 8-32 microg/mL minimal inhibitory concentration efficacies in Muller-Hinton broth against a series of clinical pathogens. Significantly, the best peptide, compound 5, A3-APO, retained full antibacterial activity in the presence of mouse serum. Across a set of eight fluoroquinolone-resistant clinical isolates, peptide 5 was 4 times more potent than ciprofloxacin. On the basis of the in vitro efficacy, toxicity, and pharmacokinetics data, we estimate that peptide 5 will be suitable for treating infections in the 3-5 mg/kg dose range.
Otvos
Laszlo
L
OLPE, LLC, 801 Mockingbird Lane, Audubon, Pennsylvania 19403, USA. lotvos@comcast.net
Wade
John D
JD
Lin
Feng
F
Condie
Barry A
BA
Hanrieder
Joerg
J
Hoffmann
Ralf
R
D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001682:Biological Availability; D019556:COS Cells; D002522:Chlorocebus aethiops; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D004926:Escherichia coli / Q000187:drug effects; D024841:Fluoroquinolones / Q000494:pharmacology*; D066298:In Vitro Techniques; D019476:Insect Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007711:Klebsiella pneumoniae / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011392:Proline / Q000737:chemistry*; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
D023181:Antimicrobial Cationic Peptides; D024841:Fluoroquinolones; D019476:Insect Proteins; C061361:apidaecin; C087710:pyrrhocoricin protein, Pyrrhocoris apterus; D011392:Proline