[show abstract][hide abstract] ABSTRACT: Drug resistance is a major obstacle to successful antibacterial chemotherapy. With the emergence of antimicrobial-resistant bacterial strains, the current drug families start to fail, and there is an urgent need for alternative agents, preferably with novel modes of action that will prevent bacteria from mounting a quick response and building resistance. Small cationic antimicrobial peptides (AMPs) are evolutionarily ancient components of the host defense system of many different unicellular and pluricel-lular organisms, from bacteria to plants, insects, fish, amphi-bians, birds, and mammals, including humans. 1 In spite of their highly diverse sequences and structural motifs, most of them show a tendency to assume amphiphilic structures in membrane environments. This feature correlates with their ability to perme-able the bacterial membranes, eventually leading to lysis of the microbial cells. 2 In addition to this membrane damaging mecha-nism, a minority of AMPs, such as those belonging to the Pro-rich group of insects and mammals, 3 are able to kill bacteria without any apparent membrane destabilization. They can effi-ciently translocate inside both prokaryotic 4,5 and eukaryotic cells, 6-8 and accumulate in the cytoplasm or in other sub cellular compartments. The mechanism of cellular uptake is not yet fully understood. However, the structural similarity of these peptides to the arginine-rich cell-penetrating peptides from protein trans-duction domains 9 and solid experimental evidence suggested a common translocation mechanism for eukaryotic cells, via en-docytic pathways. 8 Much less is known of the mechanism of penetration in bacterial cells, although a more specific translo-cation machinery has been hypothesized, involving a bacterial permease/membrane transporter. 10 Apidaecins are the largest group of proline-rich antimicro-bials known and major humoral components induced in honey-bee lymph upon bacterial infection. These cationic peptides are highly stable at a low pH (2) and high temperature (100 o C). They were the first to be studied in detail with respect to the me-chanism and the identity of the amino acid residues responsible for the antibacterial action. 10-14 The pharmacophore delivery unit architecture has been proposed to be a general feature of the proline-rich antibacterial peptide family. 15-16 However, despite a wealth of information on the amino acid residues important for function, little is known about the pharmacophore delivery unit architecture of apidaecin. So, in this research, full sequence of apidaecin and fragments that were gradually removed from N-terminal to C-terminal were synthesized and studied their growth inhibitory ability against microbial organisms in order to identify the functional region and secondary structure.