Scope and limitations of the designer proline-rich antibacterial peptide dimer, A3-APO, alone or in synergy with conventional antibiotics.
The proline-rich antimicrobial peptide dimer, A3-APO, was designed based on a statistical analysis of native antibacterial peptide and protein sequences. Analysis of a series of structural analogs failed to identify any single or multiple amino acid modification or architectural changes that would significantly improve its potential as a clinical therapeutic. However, a single chain Chex1-Arg20 version, a natural in vivo metabolite, showed a 2 to 8-fold increase in activity against test Enterobacteriaceae strains. In addition to bacterial species close to Escherichia coli in phylogeny, A3-APO analogs were able to effectively kill Pseudomonas aeruginosa and Staphylococcus saprophyticus. Antibacterial efficacy analysis together with biochemical experiments provided further evidence for a multiple mode of action of A3-APO that includes binding and inhibition of the bacterial heat shock protein DnaK. Through inactivating of resistance enzymes, A3-APO was able to recover the lost activity of conventional antibiotics including chloramphenicol, beta-lactams, sulfonamides or trimethoprim against multidrug resistant strains with partial or full synergy. However, the synergy appeared to be individual strain and small molecule drug combination-dependent.
Cassone
Marco
M
Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, United States.
Vogiatzi
Paraskevi
P
La Montagna
Raffaele
R
De Olivier Inacio
Vanessa
V
Cudic
Predrag
P
Wade
John D
JD
Otvos
Laszlo
L
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004357:Drug Synergism; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors
C539766:A3-APO peptide; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D010455:Peptides; D011392:Proline; D001616:beta-Galactosidase; C063842:dnaK protein, E coli