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 p eptide isolated from honeybees, inhibits viability of Gram-negative ba cteria; lethal activity is near immediate, independent of a convention al ''lytic'' mechanism, and involves stereoselective recognition of ta rget molecules. Here we report structural analysis of 14 naturally occ urring apidaecin-type peptides and the existence of evolutionarily con served (''constant'') regions. By detailed analysis of activities agai nst clinically relevant bacteria, we demonstrate that the diversity of the intervening (''variable'') regions confers specificity to the ant ibacterial spectrum of each homolog. As a result, apidaecin homolog-ba sed antibiograms (using 16 peptides) differ markedly between bacterial strains, contrasting the most between Yersinia enterocolitica and Cam pylobacter jejuni. Furthermore, in at least one instance, acquired res istance to apidaecin could be negated by minor substitutions in the va riable regions. The delineation in a short peptide of constant and var iable regions, responsible for, respectively, general antibacterial ca pacity and specificity of the antibacterial spectrum, is unprecedented . Taken together, we provide evidence that antibacterial spectra of ap idaecin-type peptides can be manipulated, and that, in some cases, res istance can be countered and perhaps prevented. The current findings w ill guide rational design of second generation peptide antibiotics for clinical trials.