Biodiversity of apidaecin-type peptide antibiotics. Prospects of manipulating the antibacterial spectrum and combating acquired resistance.
Insects have a unique repertoire of peptide antibiotics but, to date, prospects of clinical applications are not clear. Apidaecin, a small peptide isolated from honeybees, inhibits viability of Gram-negative bacteria; lethal activity is near immediate, independent of a conventional "lytic" mechanism, and involves stereoselective recognition of target molecules. Here we report structural analysis of 14 naturally occurring apidaecin-type peptides and the existence of evolutionarily conserved ("constant") regions. By detailed analysis of activities against clinically relevant bacteria, we demonstrate that the diversity of the intervening ("variable") regions confers specificity to the antibacterial spectrum of each homolog. As a result, apidaecin-homolog-based antibiograms (using 16 peptides) differ markedly between bacterial strains, contrasting the most between Yersinia enterocolitica and Campylobacter jejuni. Furthermore, in at least one instance, acquired resistance to apidaecin could be negated by minor substitutions in the variable regions. The delineation in a short peptide of constant and variable regions, responsible for, respectively, general antibacterial capacity and specificity of the antibacterial spectrum, is unprecedented. Taken together, we provide evidence that antibacterial spectra of apidaecin-type peptides can be manipulated, and that, in some cases, resistance can be countered and perhaps prevented. The current findings will guide rational design of second generation peptide antibiotics for clinical trials.
Casteels
P
P
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Romagnolo
J
J
Castle
M
M
Casteels-Josson
K
K
Erdjument-Bromage
H
H
Tempst
P
P
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides; D001419:Bacteria / Q000187:drug effects*; D004352:Drug Resistance, Microbial; D010450:Endopeptidases / Q000494:pharmacology; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D010455:Peptides; C061361:apidaecin; D010450:Endopeptidases