TECHNOLOGIES

The past few years witnessed an unprecedented rate of the spread of bacterial strains that are resistant to conventional antibiotics worldwide. Resistance towards a number of conventional antibiotics has increased from zero in the early fifties to almost 100% by now. This continuing spectre of bacterial resistance has driven a sustained search for new agents that possess activity on conventional antibacterial drug-resistant strains. It is widely accepted by now that although several paths are available to reach this goal, the most generalized would be the discovery and clinical development of an agent that acts on a new target that has not yet experienced selective pressure in the clinical setting. Such a target should be essential to the growth and survival of bacteria, and sufficiently different from similar macromolecules in the human or animal host.

Derivatives of native proline-rich antibacterial peptides exhibit the features required for novel types of antimicrobial drugs. Chaperone has discovered that pyrrhocoricin, a short peptide isolated from the European sap-sucking bug Pyrrhocoris apterus is non-toxic to eukaryotic cells or healthy mice and has good activity against model bacterial strains, mostly from the Enterobacteriaceae family. Native pyrrhocoricin and drosocin, another short proline-rich antibacterial peptide, kill the sensitive strains by binding to the 70 kDa bacterial heat shock protein DnaK at the D-E helix region, preventing the frequent movements of the multihelical lid over the conventional peptide-binding pocket of DnaK and thereby inhibiting chaperone-assisted protein folding. Refolding of misshapen proteins is a process needed for the life cycle of all bacteria. Remarkably, pyrrhocoricin does not bind to the human or mouse equivalents of DnaK called Hsp70 indicating the potential of this peptide and its derivatives as drug leads to treat human or veterinary bacterial infections.

While some amino acid residues in the proline-rich peptides are involved in DnaK binding, other stretches of residues serve as delivery modules to penetrate bacterial and eukaryotic cells. Thus, these native multifunctional molecules possess both properties needed to fight bacteria: ability to enter cells and bind to a unique target biopolymer. The mechanism by which the proline-rich peptide family ultimately kills bacteria is unknown for other antimicrobials currently on the market or under development.